Imidazopyridazine derivatives as modulators of TNF activity

ABSTRACT

A series of substituted imidazo[1,2-b]pyridazine derivatives of formula (I), being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

This application is the US national phase under 35 U.S.C. §371 ofinternational application PCT/EP2014/076838, filed Dec. 8, 2014, whichclaims priority to GB application 1321734.4, filed Dec. 9, 2013.

The present invention relates to a class of fused imidazole derivatives,and to their use in therapy. More particularly, this invention isconcerned with pharmacologically active substitutedimidazo[1,2-b]pyridazine derivatives. These compounds are modulators ofthe signalling of TNFα, and are accordingly of benefit as pharmaceuticalagents, especially in the treatment of adverse inflammatory andautoimmune disorders, neurological and neurodegenerative disorders, painand nociceptive disorders, cardiovascular disorders, metabolicdisorders, ocular disorders, and oncological disorders.

TNFα is the prototypical member of the Tumour Necrosis Factor (TNF)superfamily of proteins that share a primary function of regulating cellsurvival and cell death. One structural feature common to all knownmembers of the TNF superfamily is the formation of trimeric complexesthat bind to, and activate, specific TNF superfamily receptors. By wayof example, TNFα exists in soluble and transmembrane forms and signalsthrough two receptors, known as TNFR1 and TNFR2, with distinctfunctional endpoints.

Various products capable of modulating TNFα activity are alreadycommercially available. All are approved for the treatment ofinflammatory and autoimmune disorders such as rheumatoid arthritis andCrohn's disease. All currently approved products are macromolecular andact by inhibiting the binding of human TNFα to its receptor. Typicalmacromolecular TNFα inhibitors include anti-TNFα antibodies; and solubleTNFα receptor fusion proteins. Examples of commercially availableanti-TNFα antibodies include fully human antibodies such as adalimumab(Humira®) and golimumab (Simponi®), chimeric antibodies such asinfliximab (Remicade®), and pegylated Fab′ fragments such ascertolizumab pegol (Cimzia®). An example of a commercially availablesoluble TNFα receptor fusion protein is etanercept (Enbrel®).

TNF superfamily members, including TNFα itself, are implicated in avariety of physiological and pathological functions that are believed toplay a part in a range of conditions of significant medical importance(see, for example, M. G. Tansey & D. E. Szymkowski, Drug DiscoveryToday, 2009, 14, 1082-1088; and F. S. Carneiro et al., J. SexualMedicine, 2010, 7, 3823-3834).

The compounds in accordance with the present invention, being potentmodulators of human TNFα activity, are therefore beneficial in thetreatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

In addition, the compounds in accordance with the present invention maybe beneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, in one embodiment, the compounds of this invention may be usefulas radioligands in assays for detecting pharmacologically activecompounds. In an alternative embodiment, certain compounds of thisinvention may be useful for coupling to a fluorophore to providefluorescent conjugates that can be utilised in assays (e.g. afluorescence polarisation assay) for detecting pharmacologically activecompounds.

Co-pending international patent applications WO 2013/186229 (published19 Dec. 2013), WO 2014/009295 (published 16 Jan. 2014) and WO2014/009296 (also published 16 Jan. 2014) describe fused imidazolederivatives which are modulators of human TNFα activity.

None of the prior art available to date, however, discloses or suggeststhe precise structural class of imidazopyridazine derivatives asprovided by the present invention.

The compounds in accordance with the present invention potently inhibitthe binding of a fluorescence conjugate to TNFα when tested in thefluorescence polarisation assay described herein. Indeed, when tested inthat assay, the compounds of the present invention exhibit an IC₅₀ valueof 50 μM or less, generally of 20 μM or less, usually of 5 μM or less,typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nMor less, and preferably of 20 nM or less (the skilled person willappreciate that a lower IC₅₀ figure denotes a more active compound).

Certain compounds in accordance with the present invention potentlyneutralise the activity of TNFα in a commercially available HEK-293derived reporter cell line known as HEK-Blue™ CD40L. This is a stableHEK-293 transfected cell line expressing SEAP (secreted embryonicalkaline phosphatase) under the control of the IFNβ minimal promoterfused to five NF-κB binding sites. Secretion of SEAP by these cells isstimulated in a concentration-dependent manner by TNFα. When tested inthe HEK-293 bioassay, also referred to herein as the reporter geneassay, certain compounds of the present invention exhibit an IC₅₀ valueof 50 μM or less, generally of 20 μM or less, usually of 5 μM or less,typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nMor less, and preferably of 20 nM or less (as before, the skilled personwill appreciate that a lower IC₅₀ figure denotes a more activecompound).

The present invention provides a compound of formula (I) or an N-oxidethereof, or a pharmaceutically acceptable salt or solvate thereof, or aglucuronide derivative thereof, or a co-crystal thereof:

wherein

E represents a covalent bond; or E represents —O—, —S—, —S(O)—, —S(O)₂—or —N(R⁴)—; or E represents an optionally substituted straight orbranched C₁₋₄ alkylene chain;

Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— or—N(R⁵)S(O)₂—; or Q represents an optionally substituted straight orbranched C₁₋₆ alkylene chain optionally comprising one, two or threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—;

Y represents C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents;

Z represents hydrogen, halogen or trifluoromethyl; or Z represents C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents;

Z¹ represents a divalent radical derived from an aryl, C₃₋₇heterocycloalkyl or heteroaryl group;

Z² represents aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl orheteroaryl;

R¹, R² and R³ independently represent hydrogen, halogen, cyano, nitro,hydroxy, trifluoromethyl, trifluoromethoxy, —OR^(a), —SR^(a), —SOR^(a),—SO₂R^(a), —SF₅, —NR^(b)R^(c), —NR^(c)COR^(d), —NR^(c)CO₂R^(d),—NHCONR^(b)R^(c), —NR^(c)SO₂R^(e), —N(SO₂R^(e))₂, —NHSO₂NR^(b)R^(c),—COR^(d), —CO₂R^(d), —CONR^(b)R^(c), —CON(OR^(a))R^(b), —SO₂NR^(b)R^(c)or —SO(NR^(b))R^(d); or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)-alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkenyl, C₄₋₉heterobicycloalkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents;

R⁴ and R⁵ independently represent hydrogen or C₁₋₆ alkyl;

R^(a) represents C₁₋₆ alkyl, aryl, aryl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents;

R^(b) and R^(c) independently represent hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents;or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent azetidin-1-yl, pyrrolidin-1-yl,oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl,isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl,piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl orhomopiperazin-1-yl, any of which groups may be optionally substituted byone or more substituents;

R^(d) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇heterocycloalkyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; and

R^(e) represents C₁₋₆ alkyl, aryl or heteroaryl, any of which groups maybe optionally substituted by one or more substituents.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, or a glucuronide derivative thereof, or a co-crystalthereof, for use in therapy.

The present invention also provides a compound of formula (I) as definedabove or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof, or a glucuronide derivative thereof, or a co-crystalthereof, for use in the treatment and/or prevention of disorders forwhich the administration of a modulator of TNFα function is indicated.

In another aspect, the present invention provides a compound of formula(I) as defined above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, for use in the treatment and/or prevention ofan inflammatory or autoimmune disorder, a neurological orneurodegenerative disorder, pain or a nociceptive disorder, acardiovascular disorder, a metabolic disorder, an ocular disorder, or anoncological disorder.

The present invention also provides a method for the treatment and/orprevention of disorders for which the administration of a modulator ofTNFα function is indicated which comprises administering to a patient inneed of such treatment an effective amount of a compound of formula (I)as defined above or an N-oxide thereof, or a pharmaceutically acceptablesalt or solvate thereof, or a glucuronide derivative thereof, or aco-crystal thereof.

In another aspect, the present invention provides a method for thetreatment and/or prevention of an inflammatory or autoimmune disorder, aneurological or neurodegenerative disorder, pain or a nociceptivedisorder, a cardiovascular disorder, a metabolic disorder, an oculardisorder, or an oncological disorder, which comprises administering to apatient in need of such treatment an effective amount of a compound offormula (I) as defined above or an N-oxide thereof, or apharmaceutically acceptable salt or solvate thereof, or a glucuronidederivative thereof, or a co-crystal thereof.

Where any of the groups in the compounds of formula (I) above is statedto be optionally substituted, this group may be unsubstituted, orsubstituted by one or more substituents. Typically, such groups will beunsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of use in the invention or of theirpharmaceutically acceptable salts. Standard principles underlying theselection and preparation of pharmaceutically acceptable salts aredescribed, for example, in Handbook of Pharmaceutical Salts: Properties,Selection and Use, ed. P. H. Stahl & C. G. Wermuth, Wiley-VCH, 2002.Suitable pharmaceutically acceptable salts of the compounds of use inthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound of use in the invention witha solution of a pharmaceutically acceptable acid such as hydrochloricacid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid orphosphoric acid. Furthermore, where the compounds of use in theinvention carry an acidic moiety, e.g. carboxy, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g.calcium or magnesium salts; ammonium salts; and salts formed withsuitable organic ligands, e.g. quaternary ammonium salts, and megluminesalts.

The present invention includes within its scope solvates of thecompounds of formula (I) above. Such solvates may be formed with commonorganic solvents, e.g. hydrocarbon solvents such as benzene or toluene;chlorinated solvents such as chloroform or dichloromethane; alcoholicsolvents such as methanol, ethanol or isopropanol; ethereal solventssuch as diethyl ether or tetrahydrofuran; or ester solvents such asethyl acetate. Alternatively, the solvates of the compounds of formula(I) may be formed with water, in which case they will be hydrates.

The present invention also includes co-crystals within its scope. Thetechnical term “co-crystal” is used to describe the situation whereneutral molecular components are present within a crystalline compoundin a definite stoichiometric ratio. The preparation of pharmaceuticalco-crystals enables modifications to be made to the crystalline form ofan active pharmaceutical ingredient, which in turn can alter itsphysicochemical properties without compromising its intended biologicalactivity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L.Quere, RSC Publishing, 2012). Typical examples of co-crystal formers,which may be present in the co-crystal alongside the activepharmaceutical ingredient, include L-ascorbic acid, citric acid,glutaric acid, urea and nicotinamide.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Suitable alkyl groups which may be present on the compounds of use inthe invention include straight-chained and branched C₁₋₆ alkyl groups,for example C₁₋₄ alkyl groups. Typical examples include methyl and ethylgroups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyland 3-methylbutyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

The expression “C₁₋₄ alkylene chain” refers to a divalent straight orbranched alkylene chain containing 1 to 4 carbon atoms. Typical examplesinclude methylene, ethylene, methylmethylene, ethylmethylene anddimethylmethylene.

Suitable C₂₋₆ alkenyl groups include vinyl and allyl.

Suitable C₂₋₆ alkynyl groups include ethynyl, propargyl and butynyl.

The term “C₃₋₇ cycloalkyl” as used herein refers to monovalent groups of3 to 7 carbon atoms derived from a saturated monocyclic hydrocarbon, andmay comprise benzo-fused analogues thereof. Suitable C₃₋₇ cycloalkylgroups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl,indanyl, cyclohexyl and cycloheptyl.

The term “C₄₋₇ cycloalkenyl” as used herein refers to monovalent groupsof 4 to 7 carbon atoms derived from a partially unsaturated monocyclichydrocarbon. Suitable C₄₋₇ cycloalkenyl groups include cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptenyl.

The term “C₄₋₉ bicycloalkyl” as used herein refers to monovalent groupsof 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon.Typical bicycloalkyl groups include bicyclo[3.1.0]hexanyl,bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.

The term “aryl” as used herein refers to monovalent carbocyclic aromaticgroups derived from a single aromatic ring or multiple condensedaromatic rings. Suitable aryl groups include phenyl and naphthyl,preferably phenyl.

Suitable aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

The term “C₃₋₇ heterocycloalkyl” as used herein refers to saturatedmonocyclic rings containing 3 to 7 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, and may comprisebenzo-fused analogues thereof. Suitable heterocycloalkyl groups includeoxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-furanyl,dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl,oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl,tetrahydropyranyl, chromanyl, tetrahydro-thiopyranyl, piperidinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl,morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl,diazepanyl, thiadiazepanyl and azocanyl.

The term “C₃₋₇ heterocycloalkenyl” as used herein refers tomonounsaturated or polyunsaturated monocyclic rings containing 3 to 7carbon atoms and at least one heteroatom selected from oxygen, sulphurand nitrogen, and may comprise benzo-fused analogues thereof. Suitableheterocycloalkenyl groups include thiazolinyl, isothiazolinyl,imidazolinyl, dihydropyranyl, dihydrothiopyranyl and1,2,3,6-tetrahydropyridinyl.

The term “C₄₋₉ heterobicycloalkyl” as used herein corresponds to C₄₋₉bicycloalkyl wherein one or more of the carbon atoms have been replacedby one or more heteroatoms selected from oxygen, sulphur and nitrogen.Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo-[4.2.1]nonanyl.

The term “C₄₋₉ spiroheterocycloalkyl” as used herein refers to saturatedbicyclic ring systems containing 4 to 9 carbon atoms and at least oneheteroatom selected from oxygen, sulphur and nitrogen, in which the tworings are linked by a common atom. Suitable spiroheterocycloalkyl groupsinclude 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-heptanyl,2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.4]-octanyl, 2-oxa-6-azaspiro[3.5]nonanyl,7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro-[3.5]nonanyl and2,4,8-triazaspiro[4.5]decanyl.

The term “heteroaryl” as used herein refers to monovalent aromaticgroups containing at least 5 atoms derived from a single ring ormultiple condensed rings, wherein one or more carbon atoms have beenreplaced by one or more heteroatoms selected from oxygen, sulphur andnitrogen. Suitable heteroaryl groups include furyl, benzofuryl,dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl,thieno[3,4-b][1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl,pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl,oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, purinyl,imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl,thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]-pyrimidinyl,benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl,naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl,quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl andchromenyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms, typically fluorine, chlorine orbromine.

Where the compounds of formula (I) have one or more asymmetric centres,they may accordingly exist as enantiomers. Where the compounds of use inthe invention possess two or more asymmetric centres, they mayadditionally exist as diastereomers. The invention is to be understoodto extend to the use of all such enantiomers and diastereomers, and tomixtures thereof in any proportion, including racemates. Formula (I) andthe formulae depicted hereinafter are intended to represent allindividual stereoisomers and all possible mixtures thereof, unlessstated or shown otherwise. In addition, compounds of formula (I) mayexist as tautomers, for example keto (CH₂C═O)⇄enol (CH═CHOH) tautomersor amide (NHC═O)⇄hydroxyimine (N═COH) tautomers. Formula (I) and theformulae depicted hereinafter are intended to represent all individualtautomers and all possible mixtures thereof, unless stated or shownotherwise.

It is to be understood that each individual atom present in formula (I),or in the formulae depicted hereinafter, may in fact be present in theform of any of its naturally occurring isotopes, with the most abundantisotope(s) being preferred. Thus, by way of example, each individualhydrogen atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹H, ²H (deuterium) or ³H (tritium)atom, preferably ¹H. Similarly, by way of example, each individualcarbon atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

In one aspect, the present invention provides a compound of formula (I)as depicted above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, wherein

Q represents —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— or —N(R⁵)S(O)₂—; or Q representsan optionally substituted straight or branched C₁₋₆ alkylene chainoptionally comprising one, two or three heteroatom-containing linkagesindependently selected from —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁵)—,—N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—;

Z represents C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹— Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents; and

E, Y, R¹, R², R³, R⁵, Z¹ and Z² are as defined above.

In another aspect, the present invention provides a compound of formula(I) as depicted above or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, or a glucuronide derivative thereof,or a co-crystal thereof, wherein

R¹ represents halogen or cyano; or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl,aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkenyl, C₄₋₉heterobicycloalkyl, heteroaryl, heteroaryl(C₁₋₆)alkyl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents; and

E, Q, Y, Z, R² and R³ are as defined above.

Where the compounds in accordance with the invention comprise anoptionally substituted straight or branched alkylene chain, typicalvalues thereof include methylene (—CH₂—), (methyl)methylene, ethylene(—CH₂CH₂—), (ethyl)methylene, (dimethyl)-methylene, (methyl)ethylene,propylene (—CH₂CH₂CH₂—), (propyl)methylene and (dimethyl)ethylene, anyof which chains may be optionally substituted by one or moresubstituents. Suitably, such chains are unsubstituted, monosubstitutedor disubstituted. Typically, such chains are unsubstituted ormonosubstituted. In one embodiment, such chains are unsubstituted. Inanother embodiment, such chains are monosubstituted. In a furtherembodiment, such chains are disubstituted.

Examples of typical substituents on the alkylene chain which may bepresent in a compound in accordance with the invention include halogen,cyano, trifluoromethyl, oxo, hydroxy, C₁₋₆ alkoxy, carboxy(C₁₋₆)alkoxy,trifluoromethoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, carboxy, benzyloxycarbonyl, tetrazolyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl and di(C₁₋₆)alkylaminocarbonyl.

Specific examples of suitable substituents on the alkylene chain whichmay be present in a compound in accordance with the invention includefluoro, cyano, trifluoromethyl, hydroxy, methoxy, carboxymethoxy, amino,acetylamino, carboxy, benzyloxycarbonyl and tetrazolyl.

In a first embodiment, E represents a covalent bond, whereby the integerY is attached directly to the imidazole ring.

In a second embodiment, E represents —O—, —S—, —S(O)—, —S(O)₂— or—N(R⁴)—. In a first aspect of that embodiment, E represents —O—. In asecond aspect of that embodiment, E represents —S—. In a third aspect ofthat embodiment, E represents —S(O)—. In a fourth aspect of thatembodiment, E represents —S(O)₂—. In a fifth aspect of that embodiment,E represents —N(R⁴)—.

In a third embodiment, E represents an optionally substituted straightor branched C₁₋₄ alkylene chain. In a first aspect of that embodiment, Erepresents an optionally substituted methylene (—CH₂—) linkage. In asecond aspect of that embodiment, E represents an optionally substituted(methyl)methylene linkage. In a third aspect of that embodiment, Erepresents an optionally substituted (ethyl)methylene linkage.

Generally, E represents a covalent bond; or E represents —N(R⁴)—; or Erepresents an optionally substituted straight or branched C₁₋₄ alkylenechain.

Typically, E represents —N(R⁴)—; or E represents an optionallysubstituted straight or branched C₁₋₄ alkylene chain.

Suitably, E represents a covalent bond; or E represents —N(R⁴)—; or Erepresents methylene (—CH₂—), (methyl)methylene or (ethyl)methylene, anyof which groups may be optionally substituted by one or moresubstituents.

Generally, E represents —N(R⁴)—; or E represents methylene (—CH₂—) or(ethyl)methylene, either of which groups may be optionally substitutedby one or more substituents.

Appositely, E represents —N(R⁴)—, or optionally substituted methylene.

Selected examples of typical substituents on the linkage represented byE include halogen, trifluoromethyl, oxo, hydroxy, C₁₋₆ alkoxy,carboxy(C₁₋₆)alkoxy, trifluoromethoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, carboxy, benzyloxycarbonyland tetrazolyl.

Specific examples of typical substituents on the linkage represented byE include fluoro, trifluoromethyl, oxo, hydroxy, methoxy,carboxymethoxy, trifluoromethoxy, amino, methylamino, dimethylamino,acetylamino, carboxy, benzyloxycarbonyl and tetrazolyl.

Particular examples of typical substituents on E include oxo andhydroxy.

Typical values of E include —N(R⁴)—, —CH₂—, —C(O)—, —CH(OH)—,—CH(OCH₃)—, —CH(OCH₂CO₂H)—, —CH(NH₂)—, —CH(NHCOCH₃)—, —CH(CO₂H)—,—CH(CO₂benzyl)-, —CH(CH₃)—, —C(CH₃)(OH)— and —CH(CH₂CH₃)—; or E mayrepresent a covalent bond.

Selected values of E include —O—, —CH₂— and —C(O)—.

Illustrative values of E include —CH₂— and —C(O)—.

Suitable values of E include —N(R⁴)—, —CH₂— and —CH(OH)—. In oneembodiment, E represents —N(R⁴)—. In another embodiment, E represents—CH₂—. In a further embodiment, E represents —CH(OH)—.

In another embodiment, E represents —C(O)—.

In another embodiment, E represents —CH(OCH₃)—.

In another embodiment, E represents —CH(NH₂)—.

In an additional embodiment, E represents —CH(CH₃)—. In a particularaspect of that embodiment, the —CH(CH₃)— linkage represented by E is inthe (S) stereochemical configuration.

In a further embodiment, E represents —C(CH₃)(OH)—.

In a first embodiment, Q represents a covalent bond, whereby the integerZ is attached directly to the imidazole ring.

In a second embodiment, Q represents —O—, —S—, —S(O)—, —S(O)₂—,—S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— or—N(R⁵)S(O)₂—. In a first aspect of that embodiment, Q represents —O—. Ina second aspect of that embodiment, Q represents —S—. In a third aspectof that embodiment, Q represents —S(O)—. In a fourth aspect of thatembodiment, Q represents —S(O)₂—. In a fifth aspect of that embodiment,Q represents —S(O)(NR⁵)—. In a sixth aspect of that embodiment, Qrepresents —N(R⁵)—. In a seventh aspect of that embodiment, Q represents—C(O)N(R⁵)—. In an eighth aspect of that embodiment, Q represents—N(R⁵)C(O)—. In a ninth aspect of that embodiment, Q represents—S(O)₂N(R⁵)—. In a tenth aspect of that embodiment, Q represents—N(R⁵)S(O)₂—.

In a third embodiment, Q represents an optionally substituted straightor branched C₁₋₆ alkylene chain optionally comprising one, two or threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a first aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain. In a second aspect of that embodiment, Q represents an optionallysubstituted straight or branched C₁₋₆ alkylene chain comprising oneheteroatom-containing linkage independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a third aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain comprising two heteroatom-containing linkages independentlyselected from —O—, —S—, —S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—,—C(O)N(R⁵)—, —N(R⁵)C(O)—, —S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a fourthaspect of that embodiment, Q represents an optionally substitutedstraight or branched C₁₋₆ alkylene chain comprising threeheteroatom-containing linkages independently selected from —O—, —S—,—S(O)—, —S(O)₂—, —S(O)(NR⁵)—, —N(R⁵)—, —C(O)N(R⁵)—, —N(R⁵)C(O)—,—S(O)₂N(R⁵)— and —N(R⁵)S(O)₂—. In a fifth aspect of that embodiment, Qrepresents an optionally substituted straight or branched C₁₋₆ alkylenechain comprising one, two or three heteroatom-containing linkagesindependently selected from —O—, —S—, —N(R⁵)—, —C(O)N(R⁵)— and—N(R⁵)C(O)—.

Typically, Q represents a covalent bond; or Q represents —S(O)— or—S(O)₂—; or Q represents an optionally substituted straight or branchedC₁₋₆ alkylene chain optionally comprising one or twoheteroatom-containing linkages selected from —O—, —S—, —N(R⁵)—,—C(O)N(R⁵)—, and —N(R⁵)C(O)—.

Selected examples of typical substituents on the linkage represented byQ include halogen, cyano, trifluoromethyl, hydroxy, C₁₋₆ alkoxy andamino.

Specific examples of typical substituents on the linkage represented byQ include fluoro, cyano, trifluoromethyl, hydroxy, methoxy and amino.

Suitably, Q represents a covalent bond; or Q represents —S(O)—, —S(O)₂—or —N(R⁵)—; or Q represents —CH₂—, —CH(F)—, —CF₂—, —CH(CN)—, —CH(CH₃)—,—CH(OH)—, —CH(CH₂OH)—, —CH(OCH₃)—, —CH(NH₂)—, —CH₂CH₂—, —CH(OH)CH₂—,—CH(OH)CF₂—, —CH(OCH₃)CH₂—, —CH₂O—, —CH(CH₃)O—, —C(CH₃)₂O—,—CH(CH₂CH₃)O—, —CH(CF₃)O—, —CH₂S—, —CH₂S(O)—, —CH₂S(O)₂—, —CH₂N(R⁵)—,—CH₂CH₂CH₂—, —CH(OH)CH₂CH₂—, —CH(OCH₃)CH₂CH₂—, —CH₂CH₂O—, —CH₂OCH₂—,—CH₂OCH(F)—, —CH₂OCF₂—, —CH₂OCH(CH₃)—, —CH(CH₃)OCH₂—, —CH₂OC(CH₃)₂—,—C(CH₃)₂OCH₂—, —CH₂SCH₂—, —CH₂S(O)CH₂—, —CH₂S(O)₂CH₂—, —CH₂CH₂N(R⁵)—,—CH₂N(R⁵)CH₂—, —CH₂N(R⁵)C(O)—, —CH₂CH₂OCH₂—, —CH₂CH₂N(R⁵)C(O)—,—CH₂OCH₂CH₂—, —CH₂OCH₂CF₂—, —CH₂OCH₂CH(CH₃)—, —CH₂OCH(CH₃)CH₂—,—CH₂OC(CH₃)₂CH₂—, —CH₂OCH₂CH(CH₃)CH₂—, —CH₂OCH₂CH₂O—, —CH₂OCH₂C(O)N(R⁵)—or —CH₂OCH₂CH₂OCH₂—.

Appositely, Q represents a covalent bond; or Q represents —CH₂—,—CH(CN)—, —CH(OH)—, —CH(OCH₃)—, —CH₂O—, —CH₂N(R⁵)— or —CH₂OCH₂—.

More particularly, Q represents a covalent bond; or Q represents —CH₂—.

Particular values of Q include —CH₂—, —CH(OH)—, —CH₂O—, —CH₂S— and—CH₂OCH₂—. In a first embodiment, Q represents —CH₂—. In a secondembodiment, Q represents —CH(OH)—. In a third embodiment, Q represents—CH₂O—. In a fourth embodiment, Q represents —CH₂S—. In a fifthembodiment, Q represents —CH₂OCH₂—.

Generally, Y represents C₃₋₇ cycloalkyl, aryl or heteroaryl, any ofwhich groups may be optionally substituted by one or more substituents.

Typically, Y represents aryl or heteroaryl, either of which groups maybe optionally substituted by one or more substituents.

In a first embodiment, Y represents optionally substituted C₃₋₇cycloalkyl. In one aspect of that embodiment, Y represents unsubstitutedC₃₋₇ cycloalkyl. In another aspect of that embodiment, Y representsmonosubstituted C₃₋₇ cycloalkyl. In a further aspect of that embodiment,Y represents disubstituted C₃₋₇ cycloalkyl.

In a second embodiment, Y represents optionally substituted aryl. In oneaspect of that embodiment, Y represents unsubstituted aryl. In anotheraspect of that embodiment, Y represents monosubstituted aryl. In afurther aspect of that embodiment, Y represents disubstituted aryl.

In a third embodiment, Y represents optionally substituted C₃₋₇heterocycloalkyl. In one aspect of that embodiment, Y representsunsubstituted C₃₋₇ heterocycloalkyl. In another aspect of thatembodiment, Y represents monosubstituted C₃₋₇ heterocycloalkyl. In afurther aspect of that embodiment, Y represents disubstituted C₃₋₇heterocycloalkyl.

In a fourth embodiment, Y represents optionally substituted heteroaryl.In one aspect of that embodiment, Y represents unsubstituted heteroaryl.In another aspect of that embodiment, Y represents monosubstitutedheteroaryl. In a further aspect of that embodiment, Y representsdisubstituted heteroaryl.

Suitably, Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl orpyridinyl, any of which groups may be optionally substituted by one ormore substituents.

Appropriately, Y represents phenyl, thienyl or thiazolyl, any of whichgroups may be optionally substituted by one or more substituents.

Appositely, Y represents phenyl, which may be optionally substituted byone or more substituents.

Examples of optional substituents which may be present on the moiety Yinclude one, two or three substituents independently selected fromhalogen, cyano, nitro, C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, (C₁₋₆)alkylsulfonyloxy, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, arylamino, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl,C₃₋₆ heterocycloalkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆)alkylaminosulfonyl.

Typical examples of optional substituents on the moiety Y includehalogen, cyano and difluoromethoxy.

Suitable examples of optional substituents on the moiety Y includehalogen and difluoromethoxy.

Examples of particular substituents on the moiety Y include fluoro,chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl,hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, methylsulfonyloxy, amino, methylamino,tert-butylamino, dimethylamino, phenylamino, acetylamino,methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl,azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl,piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

Typical examples of particular substituents on the moiety Y includefluoro, chloro, cyano and difluoromethoxy.

Suitable examples of particular substituents on the moiety Y includechloro and difluoromethoxy.

Typical values of Y include benzocyclobutenyl, phenyl, fluorophenyl(including 2-fluorophenyl, 3-fluorophenyl and 4-fluorophenyl),chlorophenyl (including 2-chlorophenyl, 3-chlorophenyl and4-chlorophenyl), difluorophenyl (including 2,6-difluorophenyl),(chloro)(fluoro)phenyl (including 5-chloro-2-fluorophenyl and2-chloro-5-fluorophenyl), dichlorophenyl (including 2,5-dichlorophenyland 2,6-dichlorophenyl), methylphenyl (including 4-methylphenyl),dimethylphenyl (including 2,5-dimethylphenyl and 2,6-dimethylphenyl),(trifluoromethyl)phenyl [including 2-(trifluoromethyl)phenyl],(chloro)(trifluoromethyl)phenyl [including5-chloro-2-(trifluoromethyl)phenyl], (methyl)-(trifluoromethyl)phenyl[including 2-methyl-5-(trifluoromethyl)phenyl],bis(trifluoromethyl)phenyl [including 2,5-bis(trifluoromethyl)phenyl],methoxyphenyl (including 2-methoxyphenyl), (difluoromethoxy)phenyl[including 2-(difluoromethoxy)phenyl and 3-(difluoromethoxy)phenyl],(difluoromethoxy)(fluoro)phenyl [including2-(difluoromethoxy)-5-fluorophenyl and2-(difluoromethoxy)-6-fluorophenyl], (chloro)(difluoromethoxy)phenyl[including 5-chloro-2-(difluoromethoxy)phenyl and6-chloro-2-(difluoromethoxy)phenyl], (cyano)(difluoromethoxy)phenyl[including 6-cyano-2-(difluoromethoxy)phenyl], (trifluoromethoxy)phenyl[including 2-(trifluoromethoxy)-phenyl], methylsulfonyloxyphenyl,(amino)(chloro)phenyl (including 5-amino-2-chlorophenyl), methylthienyl(including 3-methylthien-2-yl), methylthiazolyl (including2-methyl-1,3-thiazol-4-yl), (chloro)(methyl)thiazolyl (including5-chloro-2-methyl-1,3-thiazol-4-yl), dimethylthiazolyl (including2,4-dimethyl-1,3-thiazol-5-yl) and pyridinyl (including pyridin-3-yl andpyridin-4-yl).

Selected values of Y include dichlorophenyl, dimethylphenyl,(difluoromethoxy)-phenyl, (difluoromethoxy)(fluoro)phenyl,methylsulfonyloxyphenyl, methylthienyl and dimethylthiazolyl.

Suitable values of Y include phenyl, dichlorophenyl and(difluoromethoxy)-phenyl.

Illustrative values of Y include dichlorophenyl and(difluoromethoxy)phenyl.

In one embodiment, Y represents 2,5-dichlorophenyl.

In another embodiment, Y represents 2,5-dimethylphenyl.

In a particular embodiment, Y represents 2-(difluoromethoxy)phenyl.

In another embodiment, Y represents (difluoromethoxy)(fluoro)phenyl.

In another embodiment, Y represents phenyl.

In another embodiment, Y represents 3-methylthien-2-yl.

In another embodiment, Y represents 2,4-dimethyl-1,3-thiazol-5-yl.

In one embodiment, Z represents hydrogen.

In another embodiment, Z is other than hydrogen.

In a selected embodiment, Z represents hydrogen; or Z represents C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents; or Z represents —Z¹—Z² or—Z¹—C(O)—Z², either of which moieties may be optionally substituted byone or more substituents.

In a further embodiment, Z represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl,C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl or heteroaryl, any ofwhich groups may be optionally substituted by one or more substituents;or Z represents —Z¹—Z² or —Z¹—C(O)—Z², either of which moieties may beoptionally substituted by one or more substituents.

Suitably, Z represents hydrogen; or Z represents C₁₋₆ alkyl, aryl orheteroaryl, any of which groups may be optionally substituted by one ormore substituents; or Z represents —Z¹—Z², which moiety may beoptionally substituted by one or more substituents.

Typically, Z represents hydrogen, fluoro or trifluoromethyl; or Zrepresents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,phenyl, tetrahydrofuranyl, pyrrolidinyl, indolinyl, tetrahydropyranyl,piperidinyl, 1,2,3,4-tetrahydroquinolinyl, morpholinyl, azocanyl,thiazolinyl, furyl, thienyl, pyrazolyl, 4,5,6,7-tetrahydroindazolyl,benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl,benzimidazolyl, [1,2,4]triazolo[1,5-a]-pyrimidinyl, tetrazolyl,pyridinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents; or Z represents —Z¹—Z² or —Z¹—C(O)—Z², either ofwhich moieties may be optionally substituted by one or moresubstituents.

The moiety Z¹ represents a divalent radical derived from an aryl, C₃₋₇heterocycloalkyl or heteroaryl group, any of which groups may beoptionally substituted by one or more substituents. Typically, themoiety Z¹ represents a divalent radical derived from a phenyl,pyrrolidinyl, piperazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolylor pyridinyl group, any of which groups may be optionally substituted byone or more substituents. Typical values of the moiety Z¹ include thegroups of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh), (Zj)and (Zk):

wherein

the symbols # represent the points of attachment of the moiety Z¹ to theremainder of the molecule; and

the asterisks (*) represent the site of attachment of optionalsubstituents.

Particular values of the moiety Z¹ include the groups of formula (Za),(Zc), (Ze), (Zf), (Zg), (Zh) and (Zj) as depicted above.

The moiety Z² represents aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl or heteroaryl, any of which groups may be optionallysubstituted by one or more substituents. Typically, Z² representsphenyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, morpholinyl,imidazolinyl, thiazolyl, imidazolyl, tetrazolyl or pyridinyl, any ofwhich groups may be optionally substituted by one or more substituents.

Examples of optional substituents which may be present on the moiety Z,Z¹ or Z² include one, two or three substituents independently selectedfrom halogen, cyano, nitro, C₁₋₆ alkyl, trifluoromethyl, oxo, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₃alkylenedioxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,di(C₁₋₆)alkylamino(C₁₋₆)alkyl, C₂₋₆ alkylcarbonylamino, C₁₋₆alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl,di(C₁₋₆)alkylaminosulfonyl, aminocarbonylamino and hydrazinocarbonyl.

Examples of particular substituents on the moiety Z, Z¹ or Z² includefluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl,trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy,trifluoromethoxy, methylenedioxy, methylthio, methylsulfinyl,methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino,dimethylaminomethyl, dimethylaminoethyl, acetylamino,methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl,tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl,dimethylaminosulfonyl, aminocarbonylamino and hydrazinocarbonyl.

Typical values of Z² include phenyl, hydroxyphenyl, oxopyrrolidinyl,dioxo-pyrrolidinyl, (hydroxy)(oxo)pyrrolidinyl,(amino)(oxo)pyrrolidinyl, (oxo)oxazolidinyl, oxoimidazolidinyl,morpholinyl, imidazolinyl, methylthiazolyl, formylthiazolyl, imidazolyl,tetrazolyl and pyridinyl.

Selected values of Z² include oxopyrrolidinyl and (oxo)oxazolidinyl. Inone embodiment, Z² represents oxopyrrolidinyl. In another embodiment, Z²represents (oxo)oxazolidinyl.

Typical values of Z include hydrogen, fluoro, trifluoromethyl, methyl,ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl,cyclopentyl, cyclohexyl, oxo-cyclohexyl, phenyl, bromophenyl,cyanophenyl, nitrophenyl, methoxyphenyl, difluoromethoxyphenyl,trifluoromethoxyphenyl, methylenedioxyphenyl, methylsulfonylphenyl,dimethylaminophenyl, acetylaminophenyl, methylsulfonylaminophenyl,carboxyphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl,dimethylaminocarbonylphenyl, aminocarbonylaminophenyl,tetrahydrofuranyl, oxopyrrolidinyl, dimethylamino-pyrrolidinyl,tert-butoxycarbonylpyrrolidinyl, indolinyl, tetrahydropyranyl,piperidinyl, ethylpiperidinyl, tert-butoxycarbonylpiperidinyl,aminocarbonylpiperidinyl, 2-oxo-3,4-dihydroquinolinyl, morpholinyl,azocanyl, oxothiazolinyl, furyl, hydroxymethylfuryl, thienyl,methylpyrazolyl, dimethylpyrazolyl, 4,5,6,7-tetrahydroindazolyl,benzoxazolyl, methylisoxazolyl, dimethylisoxazolyl, methylthiazolyl,aminothiazolyl, benzothiazolyl, methylbenzothiazolyl,aminobenzothiazolyl, imidazolyl, methylimidazolyl,methyl-benzimidazolyl, dimethyl[1,2,4]triazolo[1,5-a]pyrimidinyl,dimethylaminoethyltetrazolyl, pyridinyl, fluoropyridinyl,chloropyridinyl, cyanopyridinyl, methylpyridinyl,(cyano)-(methyl)pyridinyl, trifluoromethylpyridinyl, oxopyridinyl,methoxypyridinyl, methylsulfonylpyridinyl, dimethylaminomethylpyridinyl,acetylaminopyridinyl, carboxypyridinyl, methoxycarbonylpyridinyl,aminocarbonylpyridinyl, (aminocarbonyl)(fluoro)-pyridinyl,methylaminocarbonylpyridinyl, dimethylaminocarbonylpyridinyl,hydrazino-carbonylpyridinyl, quinolinyl, isoquinolinyl,(methyl)(oxo)phthalazinyl, pyrimidinyl, pyrazinyl,oxopyrrolidinylphenyl, dioxopyrrolidinylphenyl,(hydroxy)(oxo)pyrrolidinylphenyl, (amino)(oxo)pyrrolidinylphenyl,(oxo)oxazolidinylphenyl, oxoimidazolidinyl-phenyl, imidazolinylphenyl,methylthiazolylphenyl, formylthiazolylphenyl, imidazolyl-phenyl,tetrazolylphenyl, phenylpyrrolidinyl, hydroxyphenylpiperazinyl,(methyl)-(phenyl)pyrazolyl, oxoimidazolidinylthiazolyl,hydroxyphenyltriazolyl, morpholinyl-tetrazolyl,oxopyrrolidinylpyridinyl, (oxo)oxazolidinylpyridinyl,oxoimidazolidinyl-pyridinyl, pyridinylthiazolyl, pyridinyltetrazolyl andmorpholinylcarbonylphenyl.

Particular values of Z include hydrogen, methyl, methylsulfonylphenyl,pyridinyl, methylsulfonylpyridinyl, oxopyrrolidinylphenyl,(hydroxy)(oxo)pyrrolidinylphenyl and (oxo)oxazolidinylphenyl. In a firstembodiment, Z represents hydrogen. In a second embodiment, Z representsmethyl. In a third embodiment, Z represents methylsulfonylphenyl. In oneaspect of that embodiment, Z represents 3-(methylsulfonyl)phenyl. Inanother aspect of that embodiment, Z represents4-(methylsulfonyl)phenyl. In a fourth embodiment, Z representspyridinyl. In one aspect of that embodiment, Z represents pyridin-4-yl.In a fifth embodiment, Z represents oxopyrrolidinylphenyl. In one aspectof that embodiment, Z represents 3-(2-oxo-pyrrolidin-1-yl)phenyl. In asixth embodiment, Z represents (hydroxy)(oxo)pyrrolidinylphenyl. In oneaspect of that embodiment, Z represents3-(3-hydroxy-2-oxopyrrolidin-1-yl)phenyl. In another aspect of thatembodiment, Z represents 3-(4-hydroxy-2-oxo-pyrrolidin-1-yl)phenyl. In aseventh embodiment, Z represents (oxo)oxazolidinylphenyl. In one aspectof that embodiment, Z represents 3-(2-oxo-oxazolidinyl-3-yl)phenyl. Inan eighth embodiment, Z represents methylsulfonylpyridinyl.

Suitable values of Z include hydrogen and methyl.

Suitably, R¹, R² or R³ independently represent hydrogen, halogen, cyano,trifluoromethyl or —CO₂R^(d); or C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl-(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Examples of optional substituents which may be present on R¹, R² or R³include one, two or three substituents independently selected fromhalogen, halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, nitro,nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, difluoromethyl, trifluoromethyl,difluoroethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₃ alkylenedioxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,hydroxy(C₁₋₆)alkylamino, C₁₋₆ alkoxyamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,[(C₁₋₆)alkoxy](hydroxy)(C₁₋₆)alkylamino,[(C₁₋₆)alkylthio](hydroxy)(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,di(C₁₋₆)alkylamino(C₁₋₆)alkylamino,N-[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,hydroxy(C₁₋₆)alkyl-(C₃₋₇)cycloalkylamino,(hydroxy)[(C₃₋₇)cycloalkyl(C₁₋₆)alkyl]amino,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino,oxo(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroarylamino,heteroaryl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroaryl(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, N—[(C₁₋₆)alkyl]-N—[(C₂₋₆)alkylcarbonyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₃₋₆ alkenylcarbonylamino,bis[(C₃₋₆)alkenylcarbonyl]amino,N—[(C₁₋₆)alkyl]-N—[(C₃₋₇)cycloalkylcarbonyl]amino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkylamino, C₁₋₆alkylaminocarbonylamino, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy-(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkylcarbonyl, phenylcarbonyl,(C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω, —(C₁₋₆)alkyl-Ω,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxy(C₁₋₆)alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminocarbonyl(C₁₋₆)alkyl, aminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

By the expression “carboxylic acid isostere or prodrug moiety” is meantany functional group, structurally distinct from a carboxylic acidmoiety, that will be recognised by a biological system as being similarto, and thus capable of mimicking, a carboxylic acid moiety, or will bereadily convertible by a biological system in vivo into a carboxylicacid moiety. A synopsis of some common carboxylic acid isosteres ispresented by N. A. Meanwell in J. Med. Chem., 2011, 54, 2529-2591 (cf.in particular FIGS. 25 and 26). An alternative carboxylic acid isostereis described by N Pemberton et al. in ACS Med. Chem. Lett., 2012, 3,574-578. Typical examples of suitable carboxylic acid isostere orprodrug moieties represented by Ω include the functional groups offormula (i) to (xliii)

wherein

the asterisk (*) represents the site of attachment to the remainder ofthe molecule;

n is zero, 1 or 2;

X represents oxygen or sulphur;

R^(f) represents hydrogen, C₁₋₆ alkyl or —CH₂CH(OH)CH₂OH;

R^(g) represents C₁₋₆ alkyl, trifluoromethyl, —CH₂CH₂F, —CH₂CHF₂,—CH₂CF₃ or —CF₂CF₃;

R^(h) represents hydrogen, cyano or —CO₂R^(d), in which R^(d) is asdefined above; and

R^(j) represents hydrogen or halogen.

In one embodiment, n is zero. In another embodiment, n is 1. In afurther embodiment, n is 2.

In one embodiment, X represents oxygen. In another embodiment, Xrepresents sulphur.

In one embodiment, R^(f) represents hydrogen. In another embodiment,R^(f) represents C₁₋₆ alkyl, especially methyl. In a further embodiment,R^(f) is —CH₂CH(OH)CH₂OH.

In one embodiment, R^(g) represents C₁₋₆ alkyl, especially methyl. Inanother embodiment, R^(g) represents trifluoromethyl, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃ or —CF₂CF₃. In a first aspect of that embodiment,R^(g) represents trifluoromethyl. In a second aspect of that embodiment,R^(g) represents —CH₂CH₂F. In a third aspect of that embodiment, R^(g)represents —CH₂CHF₂. In a fourth aspect of that embodiment, R^(g)represents —CH₂CF₃. In a fifth aspect of that embodiment, R^(g)represents —CF₂CF₃.

In one embodiment, R^(h) is hydrogen. In another embodiment, R^(h)represents cyano. In a further embodiment, R^(h) represents —CO₂R^(d),especially methoxycarbonyl.

In one embodiment, R^(j) represents hydrogen. In another embodiment,R^(j) represents halogen, especially chloro.

In a selected embodiment, Ω represents tetrazolyl, especially a C-linkedtetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, inparticular a group of formula (xxiv) as depicted above.

In another embodiment, Ω represents C₁₋₆ alkylsulphonylaminocarbonyl,i.e. a moiety of formula (iii) as depicted above wherein R^(g)represents C₁₋₆ alkyl.

In another embodiment, Ω represents C₁₋₆ alkylaminosulphonyl, i.e. amoiety of formula (x) as depicted above wherein R^(g) represents C₁₋₆alkyl.

In a further embodiment, Ω represents (C₁₋₆)alkylcarbonylaminosulphonyl,i.e. a moiety of formula (v) as depicted above wherein R^(g) representsC₁₋₆ alkyl.

Typical examples of optional substituents which may be present on R¹, R²or R³ include one, two or three substituents independently selected fromC₁₋₆ alkyl, hydroxy-(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo, carboxy, C₂₋₆alkoxycarbonyl and aminosulphonyl. Additional examples includetrifluoromethyl and hydroxy.

Examples of particular substituents on R¹, R² or R³ include fluoro,chloro, bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro,nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxycyclobutyloxy, methylenedioxy, ethylenedioxy, methoxymethyl,methoxyethyl, methylthio, methylsulphinyl, methylsulphonyl,methylsulphonylethyl, oxo, amino, aminomethyl, aminoisopropyl,methylamino, ethylamino, dimethylamino, hydroxyethylamino,hydroxypropylamino, (hydroxy)(methyl)propylamino, methoxyamino,methoxyethylamino, (hydroxy)-(methoxy)(methyl)propylamino,(hydroxy)(methylthio)butylamino, N-(hydroxyethyl)-N-(methyl)amino,dimethylaminoethylamino, (dimethylamino)(methyl)propylamino,N-(dimethylaminoethyl)-N-(hydroxyethyl)amino,hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino,(cyclopropyl)(hydroxy)propylamino, morpholinylethyl-amino,oxopyrrolidinylmethylamino, ethyloxadiazolylamino,methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino,pyrimidinylmethylamino, methylpyrazolyl-methylamino, acetylamino,N-acetyl-N-methylamino, N-isopropylcarbonyl-N-methylamino,acetylaminomethyl, ethenylcarbonylamino, bis(ethenylcarbonyl)amino,N-cyclopropylcarbonyl-N-methylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino,methoxycarbonylethylamino, ethylaminocarbonylamino,butylaminocarbonylamino, methylsulphonylamino,N-methyl-N-(methylsulphonyl)amino, bis(methylsulphonyl)amino,N-(carboxymethyl)-N-methylamino, N-(carboxyethyl)-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, acetoxyisopropyl,carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl,ethoxycarbonylmethylidenyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl,tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl,methylaminocarbonyl, hydroxyethylaminocarbonyl, dimethylaminocarbonyl,aminocarbonylmethyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Typical examples of particular substituents on R¹, R² or R³ includemethyl, hydroxyisopropyl, methylsulphonyl, oxo, carboxy, methoxycarbonyland aminosulphonyl. Additional examples include trifluoromethyl andhydroxy.

Typically, R¹ represents hydrogen, halogen, cyano or —CO₂R^(d); or C₁₋₆alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkenyl, heteroaryl, (C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Suitably, R¹ represents halogen, cyano or —CO₂R^(d); or C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,heteroaryl, (C₃₋₇)heterocycloalkyl-(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

Generally, R¹ represents halogen or cyano; or C₁₋₆ alkyl, C₂₋₆ alkynyl,aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-,(C₄₋₇)cycloalkenyl-heteroaryl-, (C₄₋₉)bicycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More generally, R¹ represents halogen; or R¹ represents aryl,heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl- or(C₄₋₉)heterobicycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

In a first embodiment, R¹ represents hydrogen.

In a second embodiment, R¹ represents halogen. In one aspect of thatembodiment, R¹ represents bromo. In another aspect of that embodiment,R¹ represents chloro.

In a third embodiment, R¹ represents cyano.

In a fourth embodiment, R¹ represents —CO₂R^(d).

In a fifth embodiment, R¹ represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R¹ represents optionally substitutedethyl.

In a sixth embodiment, R¹ represents optionally substituted C₂₋₆alkynyl. In one aspect of that embodiment, R¹ represents optionallysubstituted butynyl.

In a seventh embodiment, R¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹ represents optionally substitutedphenyl.

In an eighth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkyl.

In a ninth embodiment, R¹ represents optionally substituted C₃₋₇heterocycloalkenyl.

In a tenth embodiment, R¹ represents optionally substituted heteroaryl.In selected aspects of that embodiment, R¹ represents benzofuryl,thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl orpyrazinyl, any of which groups may be optionally substituted by one ormore substituents.

In an eleventh embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-aryl-. In a first aspect of thatembodiment, R¹ represents optionally substitutedpyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R¹represents optionally substituted piperazinylmethylphenyl-.

In a twelfth embodiment, R¹ represents optionally substitutedheteroaryl(C₃₋₇)-heterocycloalkyl-. In one aspect of that embodiment, R¹represents optionally substituted pyridinylpiperazinyl-.

In a thirteenth embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted cyclohexylpyrazinyl-.

In a fourteenth embodiment, R¹ represents optionally substituted(C₄₋₇)-cycloalkenyl-heteroaryl-.

In a fifteenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹ represents optionally substituted pyrrolidinylpyridinyl-.In a second aspect of that embodiment, R¹ represents optionallysubstituted tetrahydropyranylpyridinyl-. In a third aspect of thatembodiment, R¹ represents optionally substituted piperidinylpyridinyl-.In a fourth aspect of that embodiment, R¹ represents optionallysubstituted piperazinylpyridinyl-. In a fifth aspect of that embodiment,R¹ represents optionally substituted morpholinylpyridinyl-. In a sixthaspect of that embodiment, R¹ represents optionally substitutedthiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R¹represents optionally substituted diazepanylpyridinyl-. In an eighthaspect of that embodiment, R¹ represents optionally substitutedoxetanylpyrimidinyl-. In a ninth aspect of that embodiment, R¹represents optionally substituted azetidinylpyrimidinyl-. In a tenthaspect of that embodiment, R¹ represents optionally substitutedtetrahydrofuranylpyrimidinyl-. In an eleventh aspect of that embodiment,R¹ represents optionally substituted pyrrolidinylpyrimidinyl-. In atwelfth aspect of that embodiment, R¹ represents optionally substitutedtetrahydropyranylpyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹ represents optionally substitutedthiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment,R¹ represents optionally substituted azepanylpyrimidinyl-. In aneighteenth aspect of that embodiment, R¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹ represents optionally substituted diazepanylpyrimidinyl-.In a twentieth aspect of that embodiment, R¹ represents optionallysubstituted thiadiazepanylpyrimidinyl-. In a twenty-first aspect of thatembodiment, R¹ represents optionally substituted oxetanylpyrazinyl-. Ina twenty-second aspect of that embodiment, R¹ represents optionallysubstituted piperidinylpyrazinyl-.

In a sixteenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-. In a first aspect ofthat embodiment, R¹ represents optionally substitutedmorpholinylmethylthienyl-. In a second aspect of that embodiment, R¹represents optionally substituted morpholinylethylpyrazolyl-.

In a seventeenth embodiment, R¹ represents optionally substituted(C₃₋₇)-heterocycloalkenyl-heteroaryl-.

In an eighteenth embodiment, R¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-.

In a nineteenth embodiment, R¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In a twentieth embodiment, R¹ represents optionally substituted(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl-heteroaryl-. In one aspect of thatembodiment, R¹ represents optionally substitutedcyclohexylmethylpyrimidinyl-.

In a twenty-first embodiment, R¹ represents optionally substituted(C₄₋₉)-bicycloalkyl-heteroaryl-.

Appositely, R¹ represents hydrogen, chloro, bromo, cyano or —CO₂R^(d);or ethyl, butynyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl,pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl,cyclohexylpyrazolyl, cyclohexylpyridinyl, cyclopropylpyrimidinyl,cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl,cyclohexylpyrazinyl, cyclohexylmethylpyrimidinyl, cyclohexenylpyridinyl,cyclohexenylpyrimidinyl, bicyclo[3.1.0]hexanylpyridinyl,bicyclo[3.1.0]hexanylpyrimidinyl, bicyclo[4.1.0]heptanylpyrimidinyl,bicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,tetrahydropyranylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl,oxetanylpyrimidinyl, azetidinylpyrimidinyl,tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]-pyrazinylpyrimidinyl,morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl,oxazepanylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl,oxetanylpyrazinyl, piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, 3-azabicyclo[3.1.0]hexanylpyridinyl,3-azabicyclo[3.1.0]hexanylpyridazinyl,3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,3-azabicyclo[3.1.1]heptanylpyrimidinyl,3-azabicyclo[4.1.0]heptanylpyridinyl,3-azabicyclo[4.1.0]heptanylpyrimidinyl,2-oxabicyclo[2.2.2]octanylpyrimidinyl,3-azabicyclo[3.2.1]octanylpyrimidinyl,8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl,3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,5-azaspiro[2.3]hexanylpyrimidinyl, 5-azaspiro-[2.4]heptanylpyrimidinyl,2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]-heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]-nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl or2,4,8-triazaspiro[4.5]-decanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

More particularly, R¹ represents chloro or bromo; or R¹ representsphenyl, pyrazolyl, pyrimidinyl, azetidinylpyrimidinyl,piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinylor 3-azabicyclo[3.2.1]octanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

Illustratively, R¹ represents chloro or bromo; or R¹ represents phenyl,pyrazolyl, pyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl,morpholinylpyrimidinyl or 3-azabicyclo[3.2.1]octanylpyrimidinyl, any ofwhich groups may be optionally substituted by one or more substituents.

Typical examples of optional substituents on R¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy,trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino-(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkyl-carbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl-methylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyland [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl.

Selected examples of optional substituents on R¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl,trifluoromethyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo,carboxy, C₂₋₆ alkoxycarbonyl and aminosulphonyl.

Suitable examples of optional substituents on R¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo, carboxy, C₂₋₆alkoxycarbonyl and aminosulphonyl.

Typical examples of particular substituents on R¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoroethoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylethyl,oxo, amino, aminomethyl, aminoisopropyl, methylamino, dimethylamino,methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonylmethylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, aminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Selected examples of particular substituents on R¹ include one, two orthree substituents independently selected from methyl, trifluoromethyl,hydroxy, hydroxyisopropyl, methylsulphonyl, oxo, carboxy,methoxycarbonyl and aminosulphonyl.

Suitable examples of particular substituents on R¹ include one, two orthree substituents independently selected from methyl, hydroxyisopropyl,methylsulphonyl, oxo, carboxy, methoxycarbonyl and aminosulphonyl.

In a particular embodiment, R¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹ is substituted by hydroxyisopropyl,especially 2-hydroxyprop-2-yl.

Selected values of R¹ include hydrogen, chloro, bromo, cyano, —CO₂R^(d),methoxycarbonylethyl, ethoxycarbonylethyl, hydroxybutynyl, chlorophenyl,hydroxyphenyl, methylsulphonylphenyl, aminomethylphenyl,aminoisopropylphenyl, acetylaminomethylphenyl, acetylphenyl,methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,acetylaminosulphonylphenyl, (methoxycarbonyl)(methyl)-pyrrolidinyl,oxopiperidinyl, ethoxycarbonylpiperidinyl, methylsulphonylpiperazinyl,morpholinyl, methylsulphonyl-1,2,3,6-tetrahydropyridinyl,acetyl-1,2,3,6-tetrahydropyridinyl,tert-butoxycarbonyl-1,2,3,6-tetrahydropyridinyl,methoxycarbonylmethyl-1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl,indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl,(methyl)[N-methyl-N-(methylsulfonyl)amino]pyrazolyl, methylindazolyl,dimethylisoxazolyl, hydroxyisopropylthiazolyl, methylimidazolyl,dimethylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)(methyl)pyridinyl, dimethylpyridinyl,trifluoromethylpyridinyl, ethenylpyridinyl, hydroxyisopropylpyridinyl,methoxypyridinyl, (methoxy)(methyl)pyridinyl, isopropoxypyridinyl,trifluoroethoxypyridinyl, (methyl)(trifluoroethoxy)pyridinyl,methylsulphonylpyridinyl, oxopyridinyl, (methyl)(oxo)pyridinyl,(dimethyl)(oxo)pyridinyl, aminopyridinyl, methylaminopyridinyl,dimethylaminopyridinyl, methoxyethylaminopyridinyl,N-(hydroxyethyl)-N-(methyl)aminopyridinyl,methylsulphonylaminopyridinyl, [bis(methylsulphonyl)amino]pyridinyl,carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl,fluoroisopropylpyrimidinyl, hydroxyisopropylpyrimidinyl,methoxypyrimidinyl, carboxycyclobutyloxypyrimidinyl,methylthiopyrimidinyl, methylsulphonylpyrimidinyl, oxopyrimidinyl,aminopyrimidinyl, dimethylaminopyrimidinyl,methoxyethylaminopyrimidinyl,N-(carboxyethyl)-N-(methyl)aminopyrimidinyl,carboxycyclopentylaminopyrimidinyl,carboxycyclopropylmethylaminopyrimidinyl, acetoxyisopropylpyrimidinyl,ethoxycarbonylethylpyrimidinyl, hydroxypyrazinyl,hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl,carboxycyclohexylpyrazolyl, carboxycyclohexylpyridinyl,fluoromethylcyclopropylpyrimidinyl,acetylaminomethylcyclopropylpyrimidinyl, hydroxycyclobutylpyrimidinyl,carboxycyclopentylpyrimidinyl, carboxycyclohexylpyrimidinyl,(carboxy)(methyl)cyclohexylpyrimidinyl,(carboxy)(hydroxy)cyclohexylpyrimidinyl,carboxymethylcyclohexylpyrimidinyl, ethoxycarbonylcyclohexylpyrimidinyl,(methoxycarbonyl)(methyl)cyclohexylpyrimidinyl,(ethoxycarbonyl)-(methyl)cyclohexylpyrimidinyl,carboxycyclohexylpyrazinyl, carboxycyclohexylmethylpyrimidinyl,carboxycyclohexenylpyridinyl, carboxycyclohexenylpyrimidinyl,ethoxycarbonylcyclohexenylpyrimidinyl,carboxybicyclo[3.1.0]hexanylpyridinyl,carboxybicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonylbicyclo[3.1.0]hexanylpyrimidinyl,carboxybicyclo[4.1.0]heptanylpyrimidinyl,carboxybicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,hydroxypyrrolidinylpyridinyl, hydroxytetrahydropyranylpyridinyl,piperidinylpyridinyl, acetylpiperidinylpyridinyl,(carboxy)(methyl)piperidinylpyridinyl,[(carboxy)(methyl)piperidinyl](fluoro)pyridinyl,[(carboxy)(methyl)piperidinyl](chloro)pyridinyl, piperazinylpyridinyl,(methyl)-(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl,trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl,methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl,acetylpiperazinylpyridinyl,(tert-butoxycarbonylpiperazinyl)-(methyl)pyridinyl,carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,ethoxycarbonylmethylpiperazinylpyridinyl,ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl,thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl,dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl,fluorooxetanylpyrimidinyl, hydroxyoxetanylpyrimidinyl,hydroxyazetidinylpyrimidinyl, (hydroxy)(methyl)-azetidinylpyrimidinyl,carboxyazetidinylpyrimidinyl, (tert-butoxycarbonyl)(hydroxy)-azetidinylpyrimidinyl, tetrazolylazetidinylpyrimidinyl,hydroxytetrahydrofuranylpyrimidinyl, hydroxypyrrolidinylpyrimidinyl,carboxypyrrolidinylpyrimidinyl,(carboxy)(methyl)pyrrolidinylpyrimidinyl,carboxymethylpyrrolidinylpyrimidinyl,ethoxycarbonylpyrrolidinylpyrimidinyl,fluorotetrahydropyranylpyrimidinyl, hydroxytetrahydropyranylpyrimidinyl,difluoropiperidinylpyrimidinyl, (cyano)(methyl)-piperidinylpyrimidinyl,(hydroxy)(nitromethyl)piperidinylpyrimidinyl,(hydroxy)-(methyl)piperidinylpyrimidinyl,(hydroxy)(trifluoromethyl)piperidinylpyrimidinyl,(hydroxymethyl)(methyl)piperidinylpyrimidinyl,methylsulphonylpiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl,(formyl)(methyl)piperidinylpyrimidinyl, carboxypiperidinylpyrimidinyl,(carboxy)(fluoro)piperidinylpyrimidinyl,(carboxy)(methyl)piperidinylpyrimidinyl,(carboxy)(ethyl)piperidinylpyrimidinyl,(carboxy)(trifluoromethyl)-piperidinylpyrimidinyl,(carboxy)(hydroxy)piperidinylpyrimidinyl,(carboxy)-(hydroxymethyl)piperidinylpyrimidinyl,(carboxy)(methoxy)piperidinylpyrimidinyl,(amino)(carboxy)piperidinylpyrimidinyl,carboxymethylpiperidinylpyrimidinyl,methoxycarbonylpiperidinylpyrimidinyl,ethoxycarbonylpiperidinylpyrimidinyl,(ethoxycarbonyl)(fluoro)piperidinylpyrimidinyl,(methoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethyl)(methoxycarbonyl)piperidinylpyrimidinyl,(isopropyl)-(methoxycarbonyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(methyl)piperidinylpyrimidinyl,(n-butoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(trifluoromethyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(hydroxymethyl)piperidinylpyrimidinyl,(methoxy)(methoxycarbonyl)piperidinylpyrimidinyl,(carboxy)-(methoxycarbonyl)piperidinylpyrimidinyl,(methyl)(morpholinylethoxycarbonyl)-piperidinylpyrimidinyl,ethoxycarbonylmethylpiperidinylpyrimidinyl,methylsulphonylaminocarbonylpiperidinylpyrimidinyl,acetylaminosulphonylpiperidinylpyrimidinyl,methoxyaminocarbonylpiperidinylpyrimidinyl,tetrazolylpiperidinylpyrimidinyl,hydroxyoxadiazolylpiperidinylpyrimidinyl, aminosulphonylpiperidinylpyrimidinyl, piperazinylpyrimidinyl,methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl,carboxypiperazinylpyrimidinyl, carboxyethylpiperazinylpyrimidinyl,tert-butoxycarbonylpiperazinylpyrimidinyl,tetrazolylmethylpiperazinylpyrimidinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl,hydroxymethylmorpholinylpyrimidinyl, carboxymorpholinylpyrimidinyl,(carboxy)(methyl)morpholinylpyrimidinyl,carboxymethylmorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, carboxyazepanylpyrimidinyl,carboxyoxazepanylpyrimidinyl, oxodiazepanylpyrimidinyl,(oxodiazepanyl)(trifluoromethyl)pyrimidinyl,(oxodiazepanyl)(methoxy)pyrimidinyl, (methyl)(oxo)diazepanylpyrimidinyl,dioxothiadiazepanylpyrimidinyl, hydroxyoxetanylpyrazinyl,(carboxy)(methyl)piperidinylpyrazinyl,(ethoxycarbonyl)(methyl)piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, carboxy-3-azabicyclo-[3.1.0]hexanylpyridinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[3.1.1]-heptanylpyrimidinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyridinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,(hydroxy)(methyl)-(oxo)-2-oxabicyclo[2.2.2]octanylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-8-azabicyclo-[3.2.1]octanylpyrimidinyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-3,6-diazabicyclo[3.2.2]-nonanylpyrimidinyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,carboxy-5-azaspiro[2.3]hexanylpyrimidinyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanylpyrimidinyl,carboxy-5-azaspiro[2.4]heptanylpyrimidinyl,carboxy-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl and(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanylpyrimidinyl. Additionalvalues include (hydroxy)(trifluoromethyl)azetidinylpyrimidinyl.

Representative values of R¹ include chloro, bromo, aminosulphonylphenyl,methylpyrazolyl, hydroxyisopropylpyrimidinyl,(hydroxy)(trifluoromethyl)azetidinylpyrimidinyl,carboxypiperidinylpyrimidinyl, methylsulphonylpiperazinylpyrimidinyl,oxopiperazinylpyrimidinyl, morpholinylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl andmethoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl.

Illustrative values of R¹ include chloro, bromo, aminosulphonylphenyl,methylpyrazolyl, hydroxyisopropylpyrimidinyl,carboxypiperidinylpyrimidinyl, methylsulphonylpiperazinylpyrimidinyl,oxopiperazinylpyrimidinyl, morpholinylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl andmethoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl.

Typically, R² represents hydrogen, halogen, trifluoromethyl or —OR^(a);or R² represents optionally substituted C₁₋₆ alkyl.

Typical examples of optional substituents on R² include C₂₋₆alkoxycarbonyl.

Typical examples of particular substituents on R² includeethoxycarbonyl.

In a first embodiment, R² represents hydrogen. In a second embodiment,R² represents halogen. In one aspect of that embodiment, R² representsfluoro. In another aspect of that embodiment, R² represents chloro. In athird embodiment, R² represents trifluoromethyl. In a fourth embodiment,R² represents —OR^(a). In a fifth embodiment, R² represents optionallysubstituted C₁₋₆ alkyl. In one aspect of that embodiment, R² representsunsubstituted methyl. In another aspect of that embodiment, R²represents unsubstituted ethyl. In a further aspect of that embodiment,R² represents monosubstituted methyl or monosubstituted ethyl.

Typical values of R² include hydrogen, fluoro, chloro, trifluoromethyl,—OR^(a), methyl and ethoxycarbonylethyl.

Typically, R³ represents hydrogen, halogen or C₁₋₆ alkyl.

In a first embodiment, R³ represents hydrogen. In a second embodiment,R³ represents halogen. In one aspect of that embodiment, R³ representsfluoro. In a third embodiment, R³ represents C₁₋₆ alkyl. In one aspectof that embodiment, R³ represents methyl. In another aspect of thatembodiment, R³ represents ethyl.

Suitably, R⁴ represents hydrogen or methyl.

In a first embodiment, R⁴ represents hydrogen. In a second embodiment,R⁴ represents C₁₋₆ alkyl, especially methyl.

Suitably, R⁵ represents hydrogen, methyl or ethyl.

In a first embodiment, R⁵ represents hydrogen. In a second embodiment,R⁵ represents C₁₋₆ alkyl, especially methyl or ethyl. In one aspect ofthat embodiment, R⁵ represents methyl. In another aspect of thatembodiment, R⁵ represents ethyl.

Typical examples of suitable substituents on R^(a), R^(b), R^(c), R^(d)or R^(e), or on the heterocyclic moiety —NR^(b)R^(c), include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy, C₁₋₆alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆alkylsulphonyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano,trifluoromethyl, oxo, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,C₂₋₆ alkylcarbonyloxy, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,phenylamino, pyridinylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, aminocarbonyl, C₁₋₆ alkylaminocarbonyl anddi(C₁₋₆)alkylaminocarbonyl.

Typical examples of specific substituents on R^(a), R^(b), R^(c), R^(d)or R^(e), or on the heterocyclic moiety —NR^(b)R^(c), include fluoro,chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio,methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl,aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino,methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino,acetylamino, tert-butoxycarbonylamino, acetylaminomethyl,methylsulphonylamino, aminocarbonyl, methylaminocarbonyl anddimethylaminocarbonyl.

Suitably, R^(a) represents C₁₋₆ alkyl, aryl(C₁₋₆)alkyl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents.

Selected values of R^(a) include methyl, ethyl, benzyl andisoindolylpropyl, any of which groups may be optionally substituted byone or more substituents.

Selected examples of suitable substituents on R^(a) include C₁₋₆ alkoxyand oxo.

Selected examples of specific substituents on R^(a) include methoxy andoxo.

In one embodiment, R^(a) represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R^(a) ideally represents unsubstitutedC₁₋₆ alkyl, especially methyl. In another aspect of that embodiment,R^(a) ideally represents substituted C₁₋₆ alkyl, e.g. methoxyethyl. Inanother embodiment, R^(a) represents optionally substituted aryl. In oneaspect of that embodiment, R^(a) represents unsubstituted aryl,especially phenyl. In another aspect of that embodiment, R^(a)represents monosubstituted aryl, especially methylphenyl. In anotherembodiment, R^(a) represents optionally substituted aryl(C₁₋₆)alkyl,ideally unsubstituted aryl(C₁₋₆)alkyl, especially benzyl. In a furtherembodiment, R^(a) represents optionally substituted heteroaryl. In afurther embodiment, R^(a) represents optionally substitutedheteroaryl(C₁₋₆)alkyl, e.g. dioxoisoindolylpropyl.

Specific values of R^(a) include methyl, methoxyethyl, benzyl anddioxoisoindolylpropyl.

In a particular aspect, R^(b) represents hydrogen or trifluoromethyl; orC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents.

Selected values of R^(b) include hydrogen; or C₁₋₆ alkyl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl or C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted by one or more substituents.

Typical values of R^(b) include hydrogen and C₁₋₆ alkyl.

Illustratively, R^(b) represents hydrogen or trifluoromethyl; or methyl,ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl,tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, azetidinylmethyl, tetrahydrofurylmethyl,pyrrolidinylmethyl, pyrrolidinylethyl, pyrrolidinylpropyl,thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl,piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl,morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl,indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl,imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethylor pyridinylethyl, any of which groups may be optionally substituted byone or more substituents.

Representative values of R^(b) include hydrogen; or methyl, ethyl,n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(b) include C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, hydroxy,cyano, C₂₋₆ alkoxycarbonyl, di-(C₁₋₆)alkylamino and C₂₋₆alkoxycarbonylamino.

Selected examples of specific substituents on R^(b) include methoxy,methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano,tert-butoxycarbonyl, dimethylamino and tert-butoxycarbonylamino.

Specific values of R^(b) include hydrogen, methyl, methoxyethyl,methylthioethyl, methylsulphinylethyl, methylsulphonylethyl,hydroxyethyl, cyanoethyl, dimethylaminoethyl,tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl,tert-butoxycarbonylpyrrolidinyl and morpholinylpropyl.

In one embodiment, R^(b) represents hydrogen. In another embodiment,R^(b) represents C₁₋₆ alkyl, especially methyl.

Selected values of R^(c) include hydrogen; or C₁₋₆ alkyl, C₃₋₇cycloalkyl or C₃₋₇ heterocycloalkyl, any of which groups may beoptionally substituted by one or more substituents.

In a particular aspect, R^(c) represents hydrogen, C₁₋₆ alkyl or C₃₋₇cycloalkyl.

Representative values of R^(c) include hydrogen; or methyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of whichgroups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(c) include C₂₋₆alkylcarbonyl and C₂₋₆ alkoxycarbonyl.

Selected examples of specific substituents on R^(c) include acetyl andtert-butoxycarbonyl.

Specific values of R^(c) include hydrogen, methyl, cyclobutyl,cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl andtert-butoxycarbonylpiperidinyl,

Suitably, R^(c) represents hydrogen or C₁₋₆ alkyl. In one embodiment,R^(c) is hydrogen. In another embodiment, R^(c) represents C₁₋₆ alkyl,especially methyl or ethyl, particularly methyl. In a furtherembodiment, R^(c) represents C₃₋₇ cycloalkyl, e.g. cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl.

Alternatively, the moiety —NR^(b)R^(c) may suitably representazetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl,thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl,homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may beoptionally substituted by one or more substituents.

Selected examples of suitable substituents on the heterocyclic moiety—NR^(b)R^(c) include C₁₋₆ alkyl, C₁₋₆ alkylsulphonyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, cyano, oxo, C₂₋₆ alkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, amino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkylcarbonylamino(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino and aminocarbonyl.

Selected examples of specific substituents on the heterocyclic moiety—NR^(b)R^(c) include methyl, methylsulphonyl, hydroxy, hydroxymethyl,aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino,acetylamino, acetylaminomethyl, tert-butoxycarbonylamino,methylsulphonylamino and aminocarbonyl.

Specific values of the moiety —NR^(b)R^(c) include azetidin-1-yl,hydroxyazetidin-1-yl, hydroxymethylazetidin-1-yl,(hydroxy)(hydroxymethyl)azetidin-1-yl, aminomethyl-azetidin-1-yl,cyanoazetidin-1-yl, carboxyazetidin-1-yl, aminoazetidin-1-yl,aminocarbonylazetidin-1-yl, pyrrolidin-1-yl, aminomethylpyrrolidin-1-yl,oxopyrrolidin-1-yl, acetylaminomethylpyrrolidin-1-yl,tert-butoxycarbonylaminopyrrolidin-1-yl, oxooxazolidin-3-yl,hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl,dioxo-isothiazolidin-2-yl, piperidin-1-yl, hydroxypiperidin-1-yl,hydroxymethylpiperidin-1-yl, aminopiperidin-1-yl,acetylaminopiperidin-1-yl, tert-butoxycarbonylaminopiperidin-1-yl,methylsulphonylaminopiperidin-1-yl, morpholin-4-yl, piperazin-1-yl,methylpiperazin-1-yl, methylsulphonylpiperazin-1-yl, oxopiperazin-1-yl,acetylpiperazin-1-yl, ethoxycarbonylpiperazin-1-yl andoxohomopiperazin-1-yl.

Suitably, R^(d) represents hydrogen; or C₁₋₆ alkyl, aryl or heteroaryl,any of which groups may be optionally substituted by one or moresubstituents.

Selected examples of suitable values for R^(d) include hydrogen, methyl,ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl,phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of whichgroups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(d) include halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy, oxo, C₂₋₆ alkylcarbonyloxy anddi(C₁₋₆)alkylamino.

Selected examples of particular substituents on R^(d) include fluoro,methyl, methoxy, oxo, acetoxy and dimethylamino.

In one embodiment, R^(d) represents hydrogen. In another embodiment,R^(d) represents optionally substituted C₁₋₆ alkyl. In one aspect ofthat embodiment, R^(d) ideally represents unsubstituted C₁₋₆ alkyl, e.g.methyl, ethyl, isopropyl, 2-methylpropyl or tert-butyl, especiallymethyl. In another aspect of that embodiment, R^(d) ideally representssubstituted C₁₋₆ alkyl, e.g. substituted methyl or substituted ethyl,including acetoxymethyl, dimethylaminomethyl and trifluoroethyl. Inanother embodiment, R^(d) represents optionally substituted aryl. In oneaspect of that embodiment, R^(d) represents unsubstituted aryl,especially phenyl. In another aspect of that embodiment, R^(d)represents monosubstituted aryl, especially methylphenyl. In a furtheraspect of that embodiment, R^(d) represents disubstituted aryl, e.g.dimethoxyphenyl. In a further embodiment, R^(d) represents optionallysubstituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl,methylimidazolyl or thiazolyl. In another embodiment, R^(d) representsoptionally substituted C₃₋₇ cycloalkyl, e.g. cyclopropyl or cyclobutyl.In a further embodiment, R^(d) represents optionally substituted C₃₋₇heterocycloalkyl, e.g. thiazolidinyl or oxothiazolidinyl.

Selected examples of specific values for R^(d) include hydrogen, methyl,acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl,2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl,dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl,chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.

Suitably, R^(e) represents C₁₋₆ alkyl or aryl, either of which groupsmay be optionally substituted by one or more substituents.

Selected examples of suitable substituents on R^(e) include C₁₋₆ alkyl,especially methyl.

In one embodiment, R^(e) represents optionally substituted C₁₋₆ alkyl,ideally unsubstituted C₁₋₆ alkyl, e.g. methyl or propyl, especiallymethyl. In another embodiment, R^(e) represents optionally substitutedaryl. In one aspect of that embodiment, R^(e) represents unsubstitutedaryl, especially phenyl. In another aspect of that embodiment, R^(e)represents monosubstituted aryl, especially methylphenyl. In a furtherembodiment, R^(e) represents optionally substituted heteroaryl.

Selected values of R^(e) include methyl, propyl and methylphenyl.

One sub-class of compounds according to the invention is represented bythe compounds of formula (IIA) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

R¹¹ represents halogen or cyano; or R¹¹ represents C₁₋₆ alkyl, C₂₋₆alkynyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇ heterocycloalkenyl,heteroaryl, (C₃₋₇)heterocycloalkyl-(C₁₋₆)alkyl-aryl-,heteroaryl(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉)bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents;

R¹² represents hydrogen, halogen, trifluoromethyl or optionallysubstituted C₁₋₆ alkyl;

R¹⁵ and R¹⁶ independently represent hydrogen, halogen, cyano, nitro,C₁₋₆ alkyl, trifluoromethyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, arylamino,C₂₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, formyl, C₂₋₆alkylcarbonyl, C₃₋₆ cycloalkylcarbonyl, C₃₋₆ heterocycloalkylcarbonyl,carboxy, C₂₋₆ alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl ordi(C₁₋₆)alkylaminosulfonyl; and

E, Q and Z are as defined above.

Examples of optional substituents which may be present on R¹¹ includeone, two or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, cyano(C₁₋₆)alkyl, nitro, nitro(C₁₋₆)alkyl, C₁₋₆alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl,C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₃alkylenedioxy, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl,oxo, amino, amino(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,hydroxy(C₁₋₆)alkylamino, C₁₋₆ alkoxyamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,[(C₁₋₆)alkoxy](hydroxy)(C₁₋₆)alkylamino,[(C₁₋₆)alkylthio](hydroxy)(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,di(C₁₋₆)alkylamino(C₁₋₆)alkylamino,N-[di(C₁₋₆)alkylamino(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,hydroxy(C₁₋₆)alkyl-(C₃₋₇)cycloalkylamino,(hydroxy)[(C₃₋₇)cycloalkyl(C₁₋₆)alkyl]amino,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino,oxo(C₃₋₇)heterocycloalkyl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroarylamino,heteroaryl(C₁₋₆)alkylamino, (C₁₋₆)alkylheteroaryl(C₁₋₆)alkylamino, C₂₋₆alkylcarbonylamino, N—[(C₁₋₆)alkyl]-N—[(C₂₋₆)alkylcarbonyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₃₋₆ alkenylcarbonylamino,bis[(C₃₋₆)alkenylcarbonyl]amino,N—[(C₁₋₆)alkyl]-N—[(C₃₋₇)cycloalkylcarbonyl]amino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkylamino, C₁₋₆alkylaminocarbonylamino, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy-(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₃₋₇)cycloalkylcarbonyl, phenylcarbonyl,(C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonylmethylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxy(C₁₋₆)alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminocarbonyl(C₁₋₆)alkyl, aminosulphonyl, di(C₁₋₆)alkylaminosulphonyl,(C₁₋₆)alkylsulphoximinyl and [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

Examples of particular substituents on R¹¹ include fluoro, chloro,bromo, fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitro,nitromethyl, methyl, ethyl, isopropyl, isobutyl, tert-butyl,difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxycyclobutyloxy, methylenedioxy, ethylenedioxy, methoxymethyl,methoxyethyl, methylthio, methylsulphinyl, methylsulphonyl,methylsulphonylethyl, oxo, amino, aminomethyl, aminoisopropyl,methylamino, ethylamino, dimethylamino, hydroxyethylamino,hydroxypropylamino, (hydroxy)(methyl)propylamino, methoxyamino,methoxyethylamino, (hydroxy)-(methoxy)(methyl)propylamino,(hydroxy)(methylthio)butylamino, N-(hydroxyethyl)-N-(methyl)amino,dimethylaminoethylamino, (dimethylamino)(methyl)propylamino,N-(dimethylaminoethyl)-N-(hydroxyethyl)amino,hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino,(cyclopropyl)(hydroxy)propylamino, morpholinylethyl-amino,oxopyrrolidinylmethylamino, ethyloxadiazolylamino,methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino,pyrimidinylmethylamino, methylpyrazolyl-methylamino, acetylamino,N-acetyl-N-methylamino, N-isopropylcarbonyl-N-methylamino,acetylaminomethyl, ethenylcarbonylamino, bis(ethenylcarbonyl)amino,N-cyclopropylcarbonyl-N-methylamino, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino,methoxycarbonylethylamino, ethylaminocarbonylamino,butylaminocarbonylamino, methylsulphonylamino,N-methyl-N-(methylsulphonyl)amino, bis(methylsulphonyl)amino,N-(carboxymethyl)-N-methylamino, N-(carboxyethyl)-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, acetoxyisopropyl,carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl,n-butoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, morpholinylethoxycarbonyl,ethoxycarbonylmethylidenyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl,tetrazolylmethyl, hydroxyoxadiazolyl, aminocarbonyl,methylaminocarbonyl, hydroxyethylaminocarbonyl, dimethylaminocarbonyl,aminocarbonylmethyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Generally, R¹¹ represents C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkenyl, heteroaryl,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-aryl-,heteroaryl-(C₃₋₇)heterocycloalkyl-, (C₃₋₇)cycloalkyl-heteroaryl-,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl-heteroaryl-, (C₄₋₇)cycloalkenyl-heteroaryl-,(C₄₋₉) bicycloalkyl-heteroaryl-, (C₃₋₇)heterocycloalkyl-heteroaryl-,(C₃₋₇)heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-,(C₃₋₇)heterocycloalkenyl-heteroaryl-,(C₄₋₉)heterobicycloalkyl-heteroaryl- or(C₄₋₉)spiroheterocycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

More generally, R¹¹ represents halogen; or R¹¹ represents aryl,heteroaryl, (C₃₋₇)heterocycloalkyl-heteroaryl- or(C₄₋₉)heterobicycloalkyl-heteroaryl-, any of which groups may beoptionally substituted by one or more substituents.

In a first embodiment, R¹¹ represents halogen. In one aspect of thatembodiment, R¹¹ represents bromo. In another aspect of that embodiment,R¹¹ represents chloro.

In a second embodiment, R¹¹ represents cyano.

In a third embodiment, R¹¹ represents optionally substituted C₁₋₆ alkyl.In one aspect of that embodiment, R¹¹ represents optionally substitutedethyl.

In a fourth embodiment, R¹¹ represents optionally substituted C₂₋₆alkynyl. In one aspect of that embodiment, R¹¹ represents optionallysubstituted butynyl.

In a fifth embodiment, R¹¹ represents optionally substituted aryl. Inone aspect of that embodiment, R¹¹ represents optionally substitutedphenyl.

In a sixth embodiment, R¹¹ represents optionally substituted C₃₋₇heterocycloalkyl.

In a seventh embodiment, R¹¹ represents optionally substituted C₃₋₇heterocycloalkenyl.

In an eighth embodiment, R¹¹ represents optionally substitutedheteroaryl. In selected aspects of that embodiment, R¹¹ representsbenzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl,thiazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinylor pyrazinyl, any of which groups may be optionally substituted by oneor more substituents.

In a ninth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-aryl-. In a first aspect of thatembodiment, R¹¹ represents optionally substitutedpyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R¹¹(represents optionally substituted piperazinylmethylphenyl-.

In a tenth embodiment, R¹¹ represents optionally substitutedheteroaryl(C₃₋₇)-heterocycloalkyl-. In one aspect of that embodiment,R¹¹ represents optionally substituted pyridinylpiperazinyl-.

In an eleventh embodiment, R¹¹ represents optionally substituted(C₃₋₇)cycloalkyl-heteroaryl-. In a first aspect of that embodiment, R¹¹represents optionally substituted cyclohexylpyrazolyl-. In a secondaspect of that embodiment, R¹¹ represents optionally substitutedcyclohexylpyridinyl-. In a third aspect of that embodiment, R¹¹represents optionally substituted cyclopropylpyrimidinyl-. In a fourthaspect of that embodiment, R¹¹ represents optionally substitutedcyclobutylpyrimidinyl-. In a fifth aspect of that embodiment, R¹¹represents optionally substituted cyclopentylpyrimidinyl-. In a sixthaspect of that embodiment, R¹¹ represents optionally substitutedcyclohexylpyrimidinyl-. In a seventh aspect of that embodiment, R¹¹represents optionally substituted cyclohexylpyrazinyl-.

In a twelfth embodiment, R¹¹ represents optionally substituted(C₄₋₇)cycloalkenyl-heteroaryl-.

In a thirteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl-heteroaryl-. In a first aspect of thatembodiment, R¹¹ represents optionally substitutedpyrrolidinylpyridinyl-. In a second aspect of that embodiment, R¹¹represents optionally substituted tetrahydropyranylpyridinyl-. In athird aspect of that embodiment, R¹¹ represents optionally substitutedpiperidinylpyridinyl-. In a fourth aspect of that embodiment, R¹¹represents optionally substituted piperazinylpyridinyl-. In a fifthaspect of that embodiment, R¹¹ represents optionally substitutedmorpholinylpyridinyl-. In a sixth aspect of that embodiment, R¹¹represents optionally substituted thiomorpholinylpyridinyl-. In aseventh aspect of that embodiment, R¹¹ represents optionally substituteddiazepanylpyridinyl-. In an eighth aspect of that embodiment, R¹¹represents optionally substituted oxetanylpyrimidinyl-. In a ninthaspect of that embodiment, R¹¹ represents optionally substitutedazetidinylpyrimidinyl-. In a tenth aspect of that embodiment, R¹¹represents optionally substituted tetrahydrofuranylpyrimidinyl-. In aneleventh aspect of that embodiment, R¹¹ represents optionallysubstituted pyrrolidinylpyrimidinyl-. In a twelfth aspect of thatembodiment, R¹¹ represents optionally substitutedtetrahydropyranylpyrimidinyl-. In a thirteenth aspect of thatembodiment, R¹¹ represents optionally substitutedpiperidinylpyrimidinyl-. In a fourteenth aspect of that embodiment, R¹¹represents optionally substituted piperazinylpyrimidinyl-. In afifteenth aspect of that embodiment, R¹¹ represents optionallysubstituted morpholinylpyrimidinyl-. In a sixteenth aspect of thatembodiment, R¹¹ represents optionally substitutedthiomorpholinylpyrimidinyl-. In a seventeenth aspect of that embodiment,R¹¹ represents optionally substituted azepanylpyrimidinyl-. In aneighteenth aspect of that embodiment, R¹¹ represents optionallysubstituted oxazepanylpyrimidinyl-. In a nineteenth aspect of thatembodiment, R¹¹ represents optionally substituteddiazepanylpyrimidinyl-. In a twentieth aspect of that embodiment, R¹¹represents optionally substituted thiadiazepanylpyrimidinyl-. In atwenty-first aspect of that embodiment, R¹¹ represents optionallysubstituted oxetanylpyrazinyl-. In a twenty-second aspect of thatembodiment, R¹¹ represents optionally substituted piperidinylpyrazinyl-.

In a fourteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkyl(C₁₋₆)alkyl-heteroaryl-. In a first aspect ofthat embodiment, R¹¹ represents optionally substitutedmorpholinylmethylthienyl-. In a second aspect of that embodiment, R¹¹represents optionally substituted morpholinylethylpyrazolyl-.

In a fifteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-heterocycloalkenyl-heteroaryl-.

In a sixteenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-heterobicycloalkyl-heteroaryl-.

In a seventeenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-spiroheterocycloalkyl-heteroaryl-.

In an eighteenth embodiment, R¹¹ represents optionally substituted(C₃₋₇)-cycloalkyl(C₁₋₆)alkyl-heteroaryl-. In one aspect of thatembodiment, R¹¹ represents optionally substitutedcyclohexylmethylpyrimidinyl-.

In a nineteenth embodiment, R¹¹ represents optionally substituted(C₄₋₉)-bicycloalkyl-heteroaryl-.

Appositely, R¹¹ represents chloro, bromo or cyano; or R¹¹ representsethyl, butynyl, phenyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl,pyrazolyl, indazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl,cyclohexylpyrazolyl, cyclohexylpyridinyl, cyclopropylpyrimidinyl,cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl,cyclohexylpyrazinyl, cyclohexylmethylpyrimidinyl, cyclohexenylpyridinyl,cyclohexenylpyrimidinyl, bicyclo[3.1.0]hexanylpyridinyl,bicyclo[3.1.0]hexanylpyrimidinyl, bicyclo[4.1.0]heptanylpyrimidinyl,bicyclo[2.2.2]-octanylpyrimidinyl, pyrrolidinylpyridinyl,tetrahydropyranylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl,oxetanylpyrimidinyl, azetidinylpyrimidinyl,tetrahydrofuranylpyrimidinyl, pyrrolidinylpyrimidinyl,tetrahydropyranylpyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, azepanylpyrimidinyl,oxazepanylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl,oxetanylpyrazinyl, piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, 3-azabicyclo[3.1.0]hexanylpyridinyl,3-azabicyclo[3.1.0]hexanylpyridazinyl,3-azabicyclo-[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,3-azabicyclo-[3.1.1]heptanylpyrimidinyl,3-azabicyclo[4.1.0]heptanylpyridinyl,3-azabicyclo[4.1.0]-heptanylpyrimidinyl,2-oxabicyclo[2.2.2]octanylpyrimidinyl,3-azabicyclo[3.2.1]octanylpyrimidinyl,8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo[3.2.1]octanylpyrimidinyl,3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl,3-oxa-7-azabicyclo[3.3.1]-nonanylpyrimidinyl,5-azaspiro[2.3]hexanylpyrimidinyl, 5-azaspiro[2.4]heptanylpyrimidinyl,2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl or2,4,8-triazaspiro[4.5]decanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

More particularly, R¹¹ represents chloro or bromo; or R¹¹ representsphenyl, pyrazolyl, pyrimidinyl, azetidinylpyrimidinyl,piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinylor 3-azabicyclo[3.2.1]octanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

Illustratively, R¹¹ represents chloro or bromo; or R¹¹ representsphenyl, pyrazolyl, pyrimidinyl, piperidinylpyrimidinyl,piperazinylpyrimidinyl, morpholinylpyrimidinyl or3-azabicyclo[3.2.1]octanylpyrimidinyl, any of which groups may beoptionally substituted by one or more substituents.

Typical examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from halogen, halo(C₁₋₆)alkyl,cyano, cyano(C₁₋₆)alkyl, nitro(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy,trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino,amino-(C₁₋₆)alkyl, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino,(C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, C₁₋₆ alkylsulphonylamino,N—[(C₁₋₆)alkyl]-N—[(C₁₋₆)alkylsulphonyl]amino,bis[(C₁₋₆)alkylsulphonyl]amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,formyl, C₂₋₆ alkylcarbonyl, (C₂₋₆)alkyl-carbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl-methylidenyl, acarboxylic acid isostere or prodrug moiety Ω as defined herein,—(C₁₋₆)alkyl-Ω, aminocarbonyl, aminosulphonyl, (C₁₋₆)alkylsulphoximinyland [(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl.

Selected examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl,trifluoromethyl, hydroxy, hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo,carboxy, C₂₋₆ alkoxycarbonyl and aminosulphonyl.

Suitable examples of optional substituents on R¹¹ include one, two orthree substituents independently selected from C₁₋₆ alkyl,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, oxo, carboxy, C₂₋₆alkoxycarbonyl and aminosulphonyl.

Typical examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from fluoro, chloro,fluoromethyl, fluoroisopropyl, cyano, cyanoethyl, nitromethyl, methyl,ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy,hydroxymethyl, hydroxyisopropyl, methoxy, isopropoxy, trifluoroethoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylsulphonylethyl,oxo, amino, aminomethyl, aminoisopropyl, methylamino, dimethylamino,methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, acetylaminomethyl,methylsulphonylamino, N-methyl-N-(methylsulphonyl)amino,bis(methylsulphonyl)amino, N-(carboxyethyl)-N-(methyl)amino,carboxycyclopentylamino, carboxycyclopropylmethylamino, formyl, acetyl,acetoxyisopropyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl,morpholinylethoxycarbonyl, ethoxycarbonylmethylidenyl,methylsulphonylaminocarbonyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, aminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Selected examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from methyl, trifluoromethyl,hydroxy, hydroxyisopropyl, methylsulphonyl, oxo, carboxy,methoxycarbonyl and aminosulphonyl.

Suitable examples of particular substituents on R¹¹ include one, two orthree substituents independently selected from methyl, hydroxyisopropyl,methylsulphonyl, oxo, carboxy, methoxycarbonyl and aminosulphonyl.

In a particular embodiment, R¹¹ is substituted by hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R¹¹ is substituted by hydroxyisopropyl,especially 2-hydroxyprop-2-yl.

Selected values of R¹¹ include chloro, bromo, cyano,methoxycarbonylethyl, ethoxycarbonylethyl, hydroxybutynyl, chlorophenyl,hydroxyphenyl, methylsulphonylphenyl, aminomethylphenyl,aminoisopropylphenyl, acetylaminomethylphenyl, acetylphenyl,methoxycarbonylphenyl, aminocarbonylphenyl, aminosulphonylphenyl,acetylaminosulphonylphenyl, (methoxycarbonyl)(methyl)pyrrolidinyl,oxopiperidinyl, ethoxycarbonylpiperidinyl, methylsulphonylpiperazinyl,morpholinyl, methylsulphonyl-1,2,3,6-tetrahydropyridinyl,acetyl-1,2,3,6-tetrahydropyridinyl,tert-butoxycarbonyl-1,2,3,6-tetrahydropyridinyl,methoxycarbonylmethyl-1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl,indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl,(methyl)[N-methyl-N-(methylsulfonyl)amino]pyrazolyl, methylindazolyl,dimethylisoxazolyl, hydroxyisopropylthiazolyl, methylimidazolyl,dimethylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl,methylpyridinyl, (cyano)(methyl)pyridinyl, dimethylpyridinyl,trifluoromethylpyridinyl, ethenylpyridinyl, hydroxyisopropylpyridinyl,methoxypyridinyl, (methoxy)(methyl)pyridinyl, isopropoxypyridinyl,trifluoroethoxypyridinyl, (methyl)-(trifluoroethoxy)pyridinyl,methylsulphonylpyridinyl, oxopyridinyl, (methyl)(oxo)-pyridinyl,(dimethyl)(oxo)pyridinyl, aminopyridinyl, methylaminopyridinyl,dimethylaminopyridinyl, methoxyethylaminopyridinyl,N-(hydroxyethyl)-N-(methyl)aminopyridinyl,methylsulphonylaminopyridinyl, [bis(methylsulphonyl)amino]pyridinyl,carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl,fluoroisopropylpyrimidinyl, hydroxyisopropylpyrimidinyl,methoxypyrimidinyl, carboxycyclobutyloxypyrimidinyl,methylthiopyrimidinyl, methylsulphonylpyrimidinyl, oxopyrimidinyl,aminopyrimidinyl, dimethylaminopyrimidinyl,methoxyethylaminopyrimidinyl,N-(carboxyethyl)-N-(methyl)aminopyrimidinyl,carboxycyclopentylaminopyrimidinyl,carboxycyclopropylmethylaminopyrimidinyl, acetoxyisopropylpyrimidinyl,ethoxycarbonylethylpyrimidinyl, hydroxypyrazinyl,hydroxyisopropylpyrazinyl, pyrrolidinylmethylphenyl,piperazinylmethylphenyl, pyridinylpiperazinyl,carboxycyclohexylpyrazolyl, carboxycyclohexylpyridinyl,fluoromethylcyclopropylpyrimidinyl,acetylaminomethylcyclopropylpyrimidinyl, hydroxycyclobutylpyrimidinyl,carboxycyclopentylpyrimidinyl, carboxycyclohexylpyrimidinyl,(carboxy)(methyl)cyclohexylpyrimidinyl,(carboxy)(hydroxy)cyclohexylpyrimidinyl,carboxymethylcyclohexylpyrimidinyl, ethoxycarbonylcyclohexylpyrimidinyl,(methoxycarbonyl)(methyl)-cyclohexylpyrimidinyl,(ethoxycarbonyl)(methyl)cyclohexylpyrimidinyl,carboxycyclohexylpyrazinyl, carboxycyclohexylmethylpyrimidinyl,carboxycyclohexenylpyridinyl, carboxycyclohexenylpyrimidinyl,ethoxycarbonylcyclohexenylpyrimidinyl,carboxybicyclo[3.1.0]hexanylpyridinyl,carboxybicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonylbicyclo[3.1.0]hexanylpyrimidinyl,carboxybicyclo[4.1.0]heptanylpyrimidinyl,carboxybicyclo[2.2.2]octanylpyrimidinyl, pyrrolidinylpyridinyl,hydroxypyrrolidinylpyridinyl, hydroxytetrahydropyranylpyridinyl,piperidinylpyridinyl, acetylpiperidinylpyridinyl,(carboxy)(methyl)piperidinylpyridinyl,[(carboxy)(methyl)-piperidinyl](fluoro)pyridinyl,[(carboxy)(methyl)piperidinyl](chloro)pyridinyl, piperazinylpyridinyl,(methyl)(piperazinyl)pyridinyl, cyanoethylpiperazinylpyridinyl,trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinylpyridinyl,methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl,acetylpiperazinylpyridinyl,(tert-butoxycarbonylpiperazinyl)(methyl)pyridinyl,carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl,ethoxycarbonylmethylpiperazinylpyridinyl,ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl,thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl,dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl,fluorooxetanylpyrimidinyl, hydroxyoxetanylpyrimidinyl,hydroxyazetidinylpyrimidinyl, (hydroxy)(methyl)azetidinylpyrimidinyl,carboxyazetidinylpyrimidinyl,(tert-butoxycarbonyl)(hydroxy)azetidinylpyrimidinyl,tetrazolylazetidinylpyrimidinyl, hydroxytetrahydrofuranylpyrimidinyl,hydroxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl,(carboxy)(methyl)pyrrolidinylpyrimidinyl,carboxymethylpyrrolidinylpyrimidinyl,ethoxycarbonylpyrrolidinylpyrimidinyl,fluorotetrahydropyranylpyrimidinyl, hydroxytetrahydropyranylpyrimidinyl,difluoropiperidinylpyrimidinyl, (cyano)(methyl)piperidinylpyrimidinyl,(hydroxy)(nitromethyl)piperidinylpyrimidinyl,(hydroxy)(methyl)piperidinylpyrimidinyl,(hydroxy)(trifluoromethyl)-piperidinylpyrimidinyl,(hydroxymethyl)(methyl)piperidinylpyrimidinyl,methylsulphonylpiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl,(formyl)(methyl)-piperidinylpyrimidinyl, carboxypiperidinylpyrimidinyl,(carboxy)(fluoro)piperidinylpyrimidinyl,(carboxy)(methyl)piperidinylpyrimidinyl,(carboxy)(ethyl)piperidinylpyrimidinyl,(carboxy)(trifluoromethyl)piperidinylpyrimidinyl,(carboxy)(hydroxy)-piperidinylpyrimidinyl,(carboxy)(hydroxymethyl)piperidinylpyrimidinyl,(carboxy)-(methoxy)piperidinylpyrimidinyl,(amino)(carboxy)piperidinylpyrimidinyl,carboxymethylpiperidinylpyrimidinyl,methoxycarbonylpiperidinylpyrimidinyl,ethoxycarbonylpiperidinylpyrimidinyl,(ethoxycarbonyl)(fluoro)piperidinylpyrimidinyl,(methoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethyl)(methoxycarbonyl)piperidinylpyrimidinyl,(isopropyl)(methoxycarbonyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(methyl)piperidinylpyrimidinyl,(n-butoxycarbonyl)(methyl)piperidinylpyrimidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinylpyrimidinyl,(ethoxycarbonyl)-(hydroxymethyl)piperidinylpyrimidinyl,(methoxy)(methoxycarbonyl)piperidinylpyrimidinyl,(carboxy)(methoxycarbonyl)piperidinylpyrimidinyl,(methyl)-(morpholinylethoxycarbonyl)piperidinylpyrimidinyl,ethoxycarbonylmethylpiperidinylpyrimidinyl,methylsulphonylaminocarbonylpiperidinylpyrimidinyl,acetylaminosulphonylpiperidinylpyrimidinyl,methoxyaminocarbonylpiperidinylpyrimidinyl,tetrazolylpiperidinylpyrimidinyl,hydroxyoxadiazolylpiperidinylpyrimidinyl,amino-sulphonylpiperidinylpyrimidinyl, piperazinylpyrimidinyl,methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl,carboxypiperazinylpyrimidinyl, carboxyethylpiperazinylpyrimidinyl,tert-butoxycarbonylpiperazinylpyrimidinyl,tetrazolylmethylpiperazinylpyrimidinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinylpyrimidinyl,morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl,hydroxymethylmorpholinylpyrimidinyl, carboxymorpholinylpyrimidinyl,(carboxy)(methyl)morpholinylpyrimidinyl,carboxymethylmorpholinylpyrimidinyl, thiomorpholinylpyrimidinyl,dioxothiomorpholinylpyrimidinyl, carboxyazepanylpyrimidinyl,carboxyoxazepanylpyrimidinyl, oxodiazepanylpyrimidinyl,(oxodiazepanyl)(trifluoromethyl)pyrimidinyl,(oxodiazepanyl)(methoxy)pyrimidinyl, (methyl)(oxo)diazepanylpyrimidinyl,dioxothiadiazepanylpyrimidinyl, hydroxyoxetanylpyrazinyl,(carboxy)(methyl)piperidinylpyrazinyl,(ethoxycarbonyl)(methyl)piperidinylpyrazinyl, morpholinylmethylthienyl,morpholinylethylpyrazolyl, carboxy-3-azabicyclo[3.1.0]hexanylpyridinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyridazinyl,carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl,(carboxy)(methyl)-3-azabicyclo[3.1.0]hexanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl,2-oxa-5-azabicyclo[2.2.1]heptanylpyrimidinyl,carboxy-2-oxa-5-azabicyclo-[2.2.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[3.1.1]heptanylpyrimidinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyridinyl,carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanylpyrimidinyl,ethoxycarbonyl-3-azabicyclo-[4.1.0]heptanylpyrimidinyl,(hydroxy)(methyl)(oxo)-2-oxabicyclo[2.2.2]octanylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl,oxo-8-azabicyclo[3.2.1]octanylpyrimidinyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanylpyrimidinyl,3-oxa-8-azabicyclo-[3.2.1]octanylpyrimidinyl,oxo-3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanylpyrimidinyl,carboxy-5-azaspiro[2.3]hexanylpyrimidinyl,(carboxy)(methyl)-5-azaspiro[2.3]hexanylpyrimidinyl,carboxy-5-azaspiro[2.4]heptanylpyrimidinyl,carboxy-2-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl,2-oxa-6-azaspiro[3.4]octanylpyrimidinyl,2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl,2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl and(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanylpyrimidinyl. Additionalvalues include (hydroxy)(trifluoromethyl)azetidinylpyrimidinyl.

Representative values of R¹¹ include chloro, bromo,aminosulphonylphenyl, methylpyrazolyl, hydroxyisopropylpyrimidinyl,(hydroxy)(trifluoromethyl)azetidinylpyrimidinyl,carboxypiperidinylpyrimidinyl, methylsulphonylpiperazinylpyrimidinyl,oxopiperazinylpyrimidinyl, morpholinylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl andmethoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl.

Illustrative values of R¹¹ include chloro, bromo, aminosulphonylphenyl,methylpyrazolyl, hydroxyisopropylpyrimidinyl,carboxypiperidinylpyrimidinyl, methylsulphonylpiperazinylpyrimidinyl,oxopiperazinylpyrimidinyl, morpholinylpyrimidinyl,carboxy-3-azabicyclo[3.2.1]octanylpyrimidinyl andmethoxycarbonyl-3-azabicyclo[3.2.1]octanylpyrimidinyl.

Typical examples of optional substituents on R¹² include C₂₋₆alkoxycarbonyl.

Typical examples of particular substituents on R¹² includeethoxycarbonyl.

In a first embodiment, R¹² represents hydrogen. In a second embodiment,R¹² represents halogen. In one aspect of that embodiment, R¹² representsfluoro. In another aspect of that embodiment, R¹² represents chloro. Ina third embodiment, R¹² represents trifluoromethyl. In a fourthembodiment, R¹² represents optionally substituted C₁₋₆ alkyl. In oneaspect of that embodiment, R¹² represents unsubstituted methyl. Inanother aspect of that embodiment, R¹² represents unsubstituted ethyl.In a further aspect of that embodiment, R¹² represents monosubstitutedmethyl or monosubstituted ethyl.

Typical values of R¹² include hydrogen, fluoro, chloro, trifluoromethyl,methyl and ethoxycarbonylethyl.

Typically, R¹⁵ and R¹⁶ may independently represent hydrogen, fluoro,chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl,hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino,dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl,acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl,piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl anddimethylaminosulfonyl.

Typical values of R¹⁵ include hydrogen, halogen, C₁₋₆ alkyl,trifluoromethyl, C₁₋₆ alkoxy, difluoromethoxy and trifluoromethoxy.

Suitable values of R¹⁵ include hydrogen, halogen and difluoromethoxy.

Illustrative values of R¹⁵ include halogen and difluoromethoxy.

In a first embodiment, R¹⁵ represents hydrogen. In a second embodiment,R¹⁵ represents halogen. In a first aspect of that embodiment, R¹⁵represents fluoro. In a second aspect of that embodiment, R¹⁵ representschloro. In a third embodiment, R¹⁵ represents C₁₋₆ alkyl. In one aspectof that embodiment, R¹⁵ represents methyl. In a fourth embodiment, R¹⁵represents trifluoromethyl. In a fifth embodiment, R¹⁵ represents C₁₋₆alkoxy. In one aspect of that embodiment, R¹⁵ represents methoxy. In asixth embodiment, R¹⁵ represents difluoromethoxy. In a seventhembodiment, R¹⁵ represents trifluoromethoxy.

Selected values of R¹⁵ include hydrogen, fluoro, chloro, methyl,trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.

Representative values of R¹⁵ include hydrogen, chloro anddifluoromethoxy.

Particular values of R¹⁵ include chloro and difluoromethoxy.

Typical values of R¹⁶ include hydrogen, halogen, cyano, C₁₋₆ alkyl,trifluoromethyl, difluoromethoxy and amino.

Illustrative values of R¹⁶ include hydrogen and halogen.

In a first embodiment, R¹⁶ represents hydrogen. In a second embodiment,R¹⁶ represents halogen. In a first aspect of that embodiment, R¹⁶represents fluoro. In a second aspect of that embodiment, R¹⁶ representschloro. In a third embodiment, R¹⁶ represents cyano. In a fourthembodiment, R¹⁶ represents C₁₋₆ alkyl. In one aspect of that embodiment,R¹⁶ represents methyl. In a fifth embodiment, R¹⁶ representstrifluoromethyl. In a sixth embodiment, R¹⁶ represents difluoromethoxy.In a seventh embodiment, R¹⁶ represents amino.

Selected values of R¹⁶ include hydrogen, fluoro, chloro, cyano, methyl,trifluoromethyl, difluoromethoxy and amino.

Particular values of R¹⁶ include hydrogen and chloro.

In a particular embodiment, R¹⁶ is attached at the para-position of thephenyl ring relative to the integer R¹⁵.

A particular sub-group of the compounds of formula (HA) above isrepresented by the compounds of formula (IIB) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

V represents C—R²² or N;

R²¹ represents hydrogen, halogen, halo(C₁₋₆)alkyl, cyano, C₁₋₆ alkyl,trifluoromethyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkyl,difluoromethoxy, trifluoromethoxy, trifluoroethoxy,carboxy(C₃₋₇)cycloalkyl-oxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, amino, amino-(C₁₋₆)alkyl, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)-alkyl]-N-[hydroxy(C₁₋₆)alkyl]amino, C₂₋₆ alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino-(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,C₁₋₆ alkylsulphonylamino, C₁₋₆ alkylsulphonylamino(C₁₋₆)alkyl, formyl,C₂₋₆ alkylcarbonyl, (C₂₋₆)alkylcarbonyloxy(C₁₋₆)alkyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl-methylidenyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆ alkylaminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, (C₁₋₆)alkyl-sulphoximinyl or[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl; or R²¹ represents(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₆)alkyl, (C₄₋₇)cycloalkenyl,(C₄₋₉)bicycloalkyl, (C₃₋₇)heterocycloalkyl, (C₃₋₇)heterocycloalkenyl,(C₄₋₉)heterobicycloalkyl or (C₄₋₉)spiroheterocycloalkyl, any of whichgroups may be optionally substituted by one or more substituents;

R²² represents hydrogen, halogen or C₁₋₆ alkyl;

R²³ represents hydrogen, C₁₋₆ alkyl, trifluoromethyl or C₁₋₆ alkoxy; and

E, Q, Z, R¹², R¹⁵ and R¹⁶ are as defined above.

In one embodiment, V represents C—R²². In another embodiment, Vrepresents N.

Typically, R²¹ represents hydrogen, halogen, halo(C₁₋₆)alkyl, cyano,C₁₋₆ alkyl, trifluoromethyl, C₂₋₆ alkenyl, hydroxy, hydroxy(C₁₋₆)alkyl,C₁₋₆ alkoxy, trifluoroethoxy, carboxy(C₃₋₇)cycloalkyloxy, C₁₋₆alkylthio, C₁₋₆ alkylsulphonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, (C₁₋₆)alkoxy(C₁₋₆)alkylamino,N—[(C₁₋₆)alkyl]-N-[hydroxy(C₁₋₆)alkyl]-amino,N—[(C₁₋₆)alkyl]-N-[carboxy(C₁₋₆)alkyl]amino,carboxy(C₃₋₇)cycloalkylamino, carboxy(C₃₋₇)cycloalkyl(C₁₋₆)alkylamino,C₁₋₆ alkylsulphonylamino, (C₂₋₆)alkylcarbonyl-oxy(C₁₋₆)alkyl, carboxy,morpholinyl(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl or C₂₋₆alkoxycarbonylmethylidenyl; or R²¹ represents (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl-(C₁₋₆)alkyl, (C₄₋₇)cycloalkenyl, (C₄₋₉)bicycloalkyl,(C₃₋₇)heterocycloalkyl, (C₄₋₉)heterobicycloalkyl or(C₄₋₉)spiroheterocycloalkyl, any of which groups may be optionallysubstituted by one or more substituents.

Suitably, R²¹ represents hydroxy(C₁₋₆)alkyl; or R²¹ represents(C₃₋₇)heterocycloalkyl or (C₄₋₉)heterobicycloalkyl, either of whichgroups may be optionally substituted by one or more substituents.

Where R²¹ represents an optionally substituted (C₃₋₇)cycloalkyl group,typical values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl, any of which groups may be optionally substituted byone or more substituents.

Where R²¹ represents an optionally substituted(C₃₋₇)cycloalkyl(C₁₋₆)alkyl group, a typical value is cyclohexylmethyl,which group may be optionally substituted by one or more substituents.

Where R²¹ represents an optionally substituted (C₄₋₇)cycloalkenyl group,typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl andcycloheptenyl, any of which groups may be optionally substituted by oneor more substituents.

Where R²¹ represents an optionally substituted (C₄₋₉)bicycloalkyl group,typical values include bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl andbicyclo[2.2.2]octanyl, any of which groups may be optionally substitutedby one or more substituents.

Where R²¹ represents an optionally substituted (C₃₋₇)heterocycloalkylgroup, typical values include oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl,thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl and thiadiazepanyl,any of which groups may be optionally substituted by one or moresubstituents.

Where R²¹ represents an optionally substituted (C₃₋₇)heterocycloalkenylgroup, a typical value is optionally substituted1,2,3,6-tetrahydropyridinyl.

Where R²¹ represents an optionally substituted (C₄₋₉)heterobicycloalkylgroup, typical values include 3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl,3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl,2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.2]nonanyl,3-oxa-7-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo-[4.2.1]nonanyl,any of which groups may be optionally substituted by one or moresubstituents.

Where R²¹ represents an optionally substituted(C₄₋₉)spiroheterocycloalkyl group, typical values include5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl,2-azaspiro[3.3]-heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro-[3.5]nonanyl,2-oxa-7-azaspiro[3.5]nonanyl and 2,4,8-triazaspiro[4.5]-decanyl, any ofwhich groups may be optionally substituted by one or more substituents.

Illustratively, R²¹ represents hydroxy, hydroxy(C₁₋₆)alkyl, methoxy,carboxycyclobutyloxy, methylthio, methylsulphonyl, methylamino,N-[carboxyethyl]-N-methylamino, carboxycyclopentylamino,carboxycyclopropylmethylamino or ethoxycarbonylethyl; or R²¹ representscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,cyclohexenyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl,bicyclo[2.2.2]-octanyl, oxetanyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl,hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl,thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl,3-azabicyclo[3.1.0]-hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo-[4.1.0]heptanyl,2-oxabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl,8-azabicyclo-[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl,5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]heptanyl or2-azaspiro-[3.3]heptanyl, any of which groups may be optionallysubstituted by one or more substituents.

More particularly, R²¹ represents hydroxy(C₁₋₆)alkyl; or R²¹ representsazetidinyl, piperidinyl, piperazinyl, morpholinyl or3-azabicyclo[3.2.1]octanyl, any of which groups may be optionallysubstituted by one or more substituents.

Appositely, R²¹ represents hydroxy(C₁₋₆)alkyl; or R²¹ representspiperidinyl, piperazinyl, morpholinyl or 3-azabicyclo[3.2.1]octanyl, anyof which groups may be optionally substituted by one or moresubstituents.

Examples of optional substituents which may be present on R²¹ includeone, two or three substituents independently selected from halogen,halo(C₁₋₆)alkyl, cyano, cyano-(C₁₋₆)alkyl, nitro, nitro(C₁₋₆)alkyl, C₁₋₆alkyl, trifluoromethyl, trifluoroethyl, C₂₋₆ alkenyl, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, difluoromethoxy, trifluoromethoxy,trifluoroethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, oxo, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino-(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonylamino, C₁₋₆alkylsulphonylamino, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl,morpholinyl-(C₁₋₆)alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆alkoxycarbonylmethylidenyl, a carboxylic acid isostere or prodrug moietyΩ as defined herein, —(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl,di(C₁₋₆)alkylaminosulphonyl, (C₁₋₆)alkylsulphoximinyl and[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]-sulphoximinyl.

Typical examples of optional substituents on R²¹ include one, two orthree substituents independently selected from trifluoromethyl, hydroxy,C₁₋₆ alkylsulphonyl, oxo, carboxy and C₂₋₆ alkoxycarbonyl.

Selected examples of optional substituents on R²¹ include one, two orthree substituents independently selected from C₁₋₆ alkylsulphonyl, oxo,carboxy and C₂₋₆ alkoxycarbonyl.

Suitable examples of particular substituents on R²¹ include one, two orthree substituents independently selected from fluoro, fluoromethyl,chloro, bromo, cyano, cyanomethyl, cyanoethyl, nitro, nitromethyl,methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, ethenyl,hydroxy, hydroxymethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, trifluoroethoxy, methylthio, methylsulphonyl,methylsulphonylmethyl, methylsulphonylethyl, oxo, amino, methylamino,dimethylamino, acetylamino, acetylaminomethyl, methoxycarbonylamino,ethoxycarbonylamino, tert-butoxycarbonylamino, methylsulphonylamino,formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl,ethoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl,morpholinylethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, ethoxycarbonylmethylidenyl, acetylaminosulphonyl,methoxyaminocarbonyl, tetrazolyl, tetrazolylmethyl, hydroxyoxadiazolyl,aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl,methylsulphonylaminocarbonyl, aminosulphonyl, methylaminosulphonyl,dimethylaminosulphonyl, methylsulphoximinyl and(methyl)(N-methyl)sulphoximinyl.

Typical examples of particular substituents on R²¹ include one, two orthree substituents independently selected from trifluoromethyl, hydroxy,methylsulphonyl, oxo, carboxy and methoxycarbonyl.

Selected examples of particular substituents on R²¹ include one, two orthree substituents independently selected from methylsulphonyl, oxo,carboxy and methoxycarbonyl.

Typically, R²¹ represents hydrogen, fluoro, fluoroisopropyl, cyano,methyl, trifluoromethyl, ethenyl, hydroxy, hydroxyisopropyl, methoxy,isopropoxy, trifluoroethoxy, carboxycyclobutyloxy, methylthio,methylsulphonyl, amino, methylamino, dimethylamino, methoxyethylamino,N-(hydroxyethyl)-N-(methyl)amino, N-[carboxyethyl]-N-methylamino,carboxycyclopentylamino, carboxycyclopropylmethylamino,methylsulphonylamino, acetoxyisopropyl, carboxy, ethoxycarbonylethyl,fluoromethyl-cyclopropyl, acetylaminomethylcyclopropyl,hydroxycyclobutyl, carboxycyclopentyl, carboxycyclohexyl,(carboxy)(methyl)cyclohexyl, (carboxy)(hydroxy)cyclohexyl,carboxymethylcyclohexyl, ethoxycarbonylcyclohexyl,(methoxycarbonyl)(methyl)-cyclohexyl,(ethoxycarbonyl)(methyl)cyclohexyl, carboxycyclohexylmethyl,carboxy-cyclohexenyl, ethoxycarbonylcyclohexenyl,carboxybicyclo[3.1.0]hexanyl, ethoxycarbonylbicyclo[3.1.0]hexanyl,carboxybicyclo[4.1.0]heptanyl, carboxybicyclo-[2.2.2]octanyl,fluorooxetanyl, hydroxyoxetanyl, hydroxyazetidinyl,(hydroxy)(methyl)-azetidinyl, carboxyazetidinyl,(tert-butoxycarbonyl)(hydroxy)azetidinyl, tetrazolyl-azetidinyl,hydroxytetrahydrofuranyl, pyrrolidinyl, hydroxypyrrolidinyl,carboxy-pyrrolidinyl, (carboxy)(methyl)pyrrolidinyl,carboxymethylpyrrolidinyl, ethoxycarbonyl-pyrrolidinyl,fluorotetrahydropyranyl, hydroxytetrahydropyranyl, piperidinyl,difluoro-piperidinyl, (cyano)(methyl)piperidinyl,(hydroxy)(nitromethyl)piperidinyl, (hydroxy)-(methyl)piperidinyl,(hydroxy)(trifluoromethyl)piperidinyl,(hydroxymethyl)(methyl)-piperidinyl, methylsulphonylpiperidinyl,oxopiperidinyl, (formyl)(methyl)piperidinyl, acetylpiperidinyl,carboxypiperidinyl, (carboxy)(fluoro)piperidinyl,(carboxy)(methyl)-piperidinyl, (carboxy)(ethyl)piperidinyl,(carboxy)(trifluoromethyl)piperidinyl, (carboxy)-(hydroxy)piperidinyl,(carboxy)(hydroxymethyl)piperidinyl, (carboxy)(methoxy)-piperidinyl,(amino)(carboxy)piperidinyl, carboxymethylpiperidinyl,methoxycarbonyl-piperidinyl, (methoxycarbonyl)(methyl)piperidinyl,(ethyl)(methoxycarbonyl)piperidinyl,(isopropyl)(methoxycarbonyl)piperidinyl,(methoxy)(methoxycarbonyl)piperidinyl,(carboxy)(methoxycarbonyl)piperidinyl, ethoxycarbonylpiperidinyl,(ethoxycarbonyl)-(fluoro)piperidinyl,(ethoxycarbonyl)(methyl)piperidinyl,(ethoxycarbonyl)(trifluoromethyl)piperidinyl,(ethoxycarbonyl)(hydroxymethyl)piperidinyl,(n-butoxycarbonyl)-(methyl)piperidinyl,(methyl)(morpholinylethoxycarbonyl)piperidinyl,ethoxycarbonyl-methylpiperidinyl,methylsulphonylaminocarbonylpiperidinyl,acetylaminosulphonyl-piperidinyl, methoxyaminocarbonylpiperidinyl,tetrazolylpiperidinyl, hydroxyoxadiazolyl-piperidinyl,aminosulphonylpiperidinyl, piperazinyl, cyanoethylpiperazinyl,trifluoroethyl-piperazinyl, methylsulphonylpiperazinyl,methylsulphonylethylpiperazinyl, oxopiperazinyl, acetylpiperazinyl,carboxypiperazinyl, tert-butoxycarbonylpiperazinyl,carboxymethylpiperazinyl, carboxyethylpiperazinyl,ethoxycarbonylmethylpiperazinyl, ethoxycarbonylethylpiperazinyl,tetrazolylmethylpiperazinyl,trioxohexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, morpholinyl,dimethylmorpholinyl, hydroxymethyl-morpholinyl, carboxymorpholinyl,(carboxy)(methyl)morpholinyl, carboxymethyl-morpholinyl,thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl,carboxy-azepanyl, carboxyoxazepanyl, oxodiazepanyl,(methyl)(oxo)diazepanyl, dioxo-thiadiazepanyl,carboxy-3-azabicyclo[3.1.0]hexanyl,(carboxy)(methyl)-3-azabicyclo-[3.1.0]hexanyl,methoxycarbonyl-3-azabicyclo[3.1.0]hexanyl,ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl,carboxy-2-oxa-5-azabicyclo[2.2.1]heptanyl,carboxy-3-azabicyclo[3.1.1]heptanyl,carboxy-3-azabicyclo-[4.1.0]heptanyl,methoxycarbonyl-3-azabicyclo[4.1.0]heptanyl,ethoxycarbonyl-3-azabicyclo[4.1.0]heptanyl,(hydroxy)(methyl)(oxo)-2-oxabicyclo[2.2.2]octanyl,carboxy-3-azabicyclo[3.2.1]octanyl,methoxycarbonyl-3-azabicyclo[3.2.1]octanyl,oxo-8-azabicyclo[3.2.1]octanyl,ethoxycarbonylmethylidenyl-8-azabicyclo[3.2.1]octanyl,3-oxa-8-azabicyclo[3.2.1]octanyl, oxo-3,6-diazabicyclo[3.2.2]nonanyl,carboxy-3-oxa-7-azabicyclo[3.3.1]nonanyl,carboxy-5-azaspiro[2.3]hexanyl,(carboxy)(methyl)-5-azaspiro-[2.3]hexanyl,carboxy-5-azaspiro[2.4]heptanyl, carboxy-2-azaspiro[3.3]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl,2-oxa-6-azaspiro[3.5]nonanyl, 2-oxa-7-azaspiro[3.5]nonanyl or(dioxo)(methyl)-2,4,8-triazaspiro[4.5]decanyl. Additionally, R²¹ mayrepresent (hydroxy)(trifluoromethyl)azetidinyl.

Selected values of R²¹ include hydroxyisopropyl,(hydroxy)(trifluoromethyl)-azetidinyl, carboxypiperidinyl,methylsulphonylpiperazinyl, oxopiperazinyl, morpholinyl,carboxy-3-azabicyclo[3.2.1]octanyl andmethoxycarbonyl-3-azabicyclo[3.2.1]octanyl.

Illustrative values of R²¹ include hydroxyisopropyl, carboxypiperidinyl,methylsulphonylpiperazinyl, oxopiperazinyl, morpholinyl,carboxy-3-azabicyclo-[3.2.1]octanyl andmethoxycarbonyl-3-azabicyclo[3.2.1]octanyl.

In a particular embodiment, R²¹ represents hydroxy(C₁₋₆)alkyl. In oneaspect of that embodiment, R²¹ represents hydroxyisopropyl, especially2-hydroxyprop-2-yl.

Generally, R²² represents hydrogen or C₁₋₆ alkyl.

Suitably, R²² represents hydrogen, chloro or methyl.

Typically, R²² represents hydrogen or methyl.

In one embodiment, R²² represents hydrogen. In another embodiment, R²²represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R²²represents halogen. In one aspect of that embodiment, R²² representsfluoro. In another aspect of that embodiment, R²² represents chloro.

Generally, R²³ represents hydrogen or C₁₋₆ alkyl.

Suitably, R²³ represents hydrogen, methyl, trifluoromethyl or methoxy.

Typically, R²³ represents hydrogen or methyl.

In one embodiment, R²³ represents hydrogen. In another embodiment, R²³represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R²³represents trifluoromethyl. In an additional embodiment, R²³ representsC₁₋₆ alkoxy, especially methoxy.

Particular sub-groups of the compounds of formula (IIB) above arerepresented by the compounds of formula (IIC), (IID), (IIE), (IIF),(IIG), (IIH), (III), (IIK) and (IIL), and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

T represents —CH₂— or —CH₂CH₂—;

U represents C(O) or S(O)₂;

W represents O, S, S(O), S(O)₂, S(O)(NR⁵), N(R³¹) or C(R³²)(R³³);

-M- represents —CH₂— or —CH₂CH₂—;

R³¹ represents hydrogen, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl, trifluoromethyl,trifluoroethyl, C₁₋₆ alkylsulphonyl, (C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl,formyl, C₂₋₆ alkylcarbonyl, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, a carboxylic acidisostere or prodrug moiety Ω, —(C₁₋₆)alkyl-Ω, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl ordi(C₁₋₆)alkylaminosulphonyl;

R³² represents hydrogen, halogen, cyano, hydroxy, hydroxy(C₁₋₆)alkyl,C₁₋₆ alkylsulphonyl, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminosulphonyl, (C₁₋₆)alkyl-sulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl, a carboxylic acid isostere orprodrug moiety Ω, or —(C₁₋₆)alkyl-Ω;

R³³ represents hydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, hydroxy,hydroxy-(C₁₋₆)alkyl, C₁₋₆ alkoxy, amino or carboxy;

R³⁴ represents hydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₆ alkylsulphinyl, C₁₋₆ alkylsulphonyl, amino, C₁₋₆alkylamino, di(C₁₋₆)alkylamino, (C₂₋₆)alkylcarbonylamino,(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, (C₁₋₆)alkylsulphonylamino or(C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl; and

V, E, Q, Z, R⁵, R¹², R¹⁵, R¹⁶, R²³ and Ω are as defined above.

In a first embodiment, T represents —CH₂—. In a second embodiment, Trepresents —CH₂CH₂—.

In a first embodiment, U represents C(O). In a second embodiment, Urepresents S(O)₂.

Generally, W represents O, S(O)₂, N(R³¹) or C(R³²)(R³³).

Typically, W represents O, N(R³¹) or C(R³²)(R³³).

In a first embodiment, W represents O. In a second embodiment, Wrepresents S. In a third embodiment, W represents S(O). In a fourthembodiment, W represents S(O)₂. In a fifth embodiment, W representsS(O)(NR⁵). In a sixth embodiment, W represents N(R³¹). In a seventhembodiment, W represents C(R³²)(R³³).

In one embodiment, -M- represents —CH₂—. In another embodiment, -M-represents —CH₂CH₂—.

Typically, R³¹ represents hydrogen, cyano(C₁₋₆)alkyl, C₁₋₆ alkyl,trifluoromethyl, trifluoroethyl, C₁₋₆ alkylsulphonyl,(C₁₋₆)alkylsulphonyl(C₁₋₆)alkyl, formyl, C₂₋₆ alkylcarbonyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl-(C₁₋₆)alkyl, tetrazolyl(C₁₋₆)alkyl, aminocarbonyl, C₁₋₆alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl, aminosulphonyl, C₁₋₆alkylaminosulphonyl or di(C₁₋₆)alkylaminosulphonyl.

Suitably, R³¹ represents C₁₋₆ alkylsulphonyl.

Typical values of R³¹ include hydrogen, cyanoethyl, methyl, ethyl,isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl,methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl,carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolylmethyl,aminocarbonyl, methylamino-carbonyl, dimethylaminocarbonyl,aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl.

A particular value of R³¹ is methylsulphonyl.

Generally, R³² represents halogen, carboxy, carboxy(C₁₋₆)alkyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, a carboxylic acidisostere or prodrug moiety Ω, or —(C₁₋₆)alkyl-Ω.

Typically, R³² represents hydrogen, halogen, cyano, hydroxy,hydroxy(C₁₋₆)alkyl, C₁₋₆ alkylsulphonyl, formyl, carboxy,carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,aminosulphonyl, (C₁₋₆)alkylsulphoximinyl,[(C₁₋₆)alkyl][N—(C₁₋₆)alkyl]sulphoximinyl(C₁₋₆)alkylsulphonylaminocarbonyl, (C₂₋₆)alkylcarbonylaminosulphonyl,(C₁₋₆)alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl.

Typical values of R³² include hydrogen, fluoro, cyano, hydroxy,hydroxymethyl, methylsulphonyl, formyl, carboxy, carboxymethyl,carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, aminosulphonyl, methylsulphoximinyl,(methyl)(N-methyl)sulphoximinyl, methylsulphonylaminocarbonyl,acetylaminosulphonyl, methoxyaminocarbonyl, tetrazolyl andhydroxyoxadiazolyl.

In a selected embodiment, R³² represents carboxy.

Generally, R³³ represents hydrogen, halogen or C₁₋₆ alkyl.

Suitably, R³³ represents hydrogen or C₁₋₆ alkyl.

Selected values of R³³ include hydrogen, fluoro, methyl, ethyl,isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, amino andcarboxy.

Selected values of R³³ include hydrogen and methyl.

In a first embodiment, R³³ represents hydrogen. In a second embodiment,R³³ represents halogen. In one aspect of that embodiment, R³³ representsfluoro. In a third embodiment, R³³ represents C₁₋₆ alkyl. In a firstaspect of that embodiment, R³³ represents methyl. In a second aspect ofthat embodiment, R³³ represents ethyl. In a third aspect of thatembodiment, R³³ represents isopropyl. In a fourth embodiment, R³³represents trifluoromethyl. In a fifth embodiment, R³³ representshydroxy. In a sixth embodiment, R³³ represents hydroxy(C₁₋₆)alkyl. Inone aspect of that embodiment, R³³ represents hydroxymethyl. In aseventh embodiment, R³³ represents C₁₋₆ alkoxy. In one aspect of thatembodiment, R³³ represents methoxy. In an eighth embodiment, R³³represents amino. In a ninth embodiment, R³³ represents carboxy.

In a first embodiment, R³⁴ represents hydrogen. In a second embodiment,R³⁴ represents halogen. In one aspect of that embodiment, R³⁴ representsfluoro. In a third embodiment, R³⁴ represents halo(C₁₋₆)alkyl. In oneaspect of that embodiment, R³⁴ represents fluoromethyl. In a fourthembodiment, R³⁴ represents hydroxy. In a fifth embodiment, R³⁴represents C₁₋₆ alkoxy, especially methoxy. In a sixth embodiment, R³⁴represents C₁₋₆ alkylthio, especially methylthio. In a seventhembodiment, R³⁴ represents C₁₋₆ alkylsulphinyl, especiallymethylsulphinyl. In an eighth embodiment, R³⁴ represents C₁₋₆alkylsulphonyl, especially methylsulphonyl. In a ninth embodiment, R³⁴represents amino. In a tenth embodiment, R³⁴ represents C₁₋₆ alkylamino,especially methylamino. In an eleventh embodiment, R³⁴ representsdi(C₁₋₆)alkylamino, especially dimethylamino. In a twelfth embodiment,R³⁴ represents (C₂₋₆)alkylcarbonylamino, especially acetylamino. In athirteenth embodiment, R³⁴ represents(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl, especially acetylaminomethyl. In afourteenth embodiment, R³⁴ represents (C₁₋₆)alkylsulphonylamino,especially methylsulphonylamino. In a fifteenth embodiment, R³⁴represents (C₁₋₆)alkylsulphonylamino(C₁₋₆)alkyl, especiallymethylsulphonylaminomethyl.

Typically, R³⁴ represents hydrogen, halogen, halo(C₁₋₆)alkyl, hydroxy or(C₂₋₆)alkylcarbonylamino(C₁₋₆)alkyl.

Selected values of R³⁴ include hydrogen, fluoro, fluoromethyl, hydroxy,methoxy, methylthio, methylsulphinyl, methylsulphonyl, amino,methylamino, dimethylamino and acetylaminomethyl.

Particular values of R³⁴ include hydrogen, fluoro, fluoromethyl, hydroxyand acetylaminomethyl.

Suitably, R³⁴ represents hydrogen or hydroxy.

An alternative sub-class of compounds according to the invention isrepresented by the compounds of formula (IIM) and N-oxides thereof, andpharmaceutically acceptable salts and solvates thereof, and glucuronidederivatives thereof, and co-crystals thereof:

wherein

E, Q, Z, W, R¹², R¹⁵, R¹⁶ and R²¹ are as defined above.

With specific reference to formula (IIM), the integer W is suitably 0, Sor N—R³¹, especially S or N—R³¹.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof, and co-crystals thereof.

The compounds in accordance with the present invention are beneficial inthe treatment and/or prevention of various human ailments. These includeautoimmune and inflammatory disorders; neurological andneurodegenerative disorders; pain and nociceptive disorders;cardiovascular disorders; metabolic disorders; ocular disorders; andoncological disorders.

Inflammatory and autoimmune disorders include systemic autoimmunedisorders, autoimmune endocrine disorders and organ-specific autoimmunedisorders. Systemic autoimmune disorders include systemic lupuserythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis,polymyositis, scleroderma, multiple sclerosis, systemic sclerosis,ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatoryarthritis, juvenile inflammatory arthritis, juvenile idiopathicarthritis (including oligoarticular and polyarticular forms thereof),anaemia of chronic disease (ACD), Still's disease (juvenile and/or adultonset), Behçcet's disease and Sjögren's syndrome. Autoimmune endocrinedisorders include thyroiditis. Organ-specific autoimmune disordersinclude Addison's disease, haemolytic or pernicious anaemia, acutekidney injury (AKI; including cisplatin-induced AKI), diabeticnephropathy (DN), obstructive uropathy (including cisplatin-inducedobstructive uropathy), glomerulonephritis (including Goodpasture'ssyndrome, immune complex-mediated glomerulonephritis and antineutrophilcytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupusnephritis (LN), minimal change disease, Graves' disease, idiopathicthrombocytopenic purpura, inflammatory bowel disease (including Crohn'sdisease, ulcerative colitis, indeterminate colitis and pouchitis),pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliarycirrhosis, autoimmune pneumonitis, autoimmune carditis, myastheniagravis, spontaneous infertility, osteoporosis, osteopenia, erosive bonedisease, chondritis, cartilage degeneration and/or destruction,fibrosing disorders (including various forms of hepatic and pulmonaryfibrosis), asthma, rhinitis, chronic obstructive pulmonary disease(COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy(including Duchenne muscular dystrophy) and organ transplant rejection(including kidney allograft rejection).

Neurological and neurodegenerative disorders include Alzheimer'sdisease, Parkinson's disease, Huntington's disease, ischaemia, stroke,amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizuresand epilepsy.

Cardiovascular disorders include thrombosis, cardiac hypertrophy,hypertension, irregular contractility of the heart (e.g. during heartfailure), and sexual disorders (including erectile dysfunction andfemale sexual dysfunction). Modulators of TNFα function may also be ofuse in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).

Metabolic disorders include diabetes (including insulin-dependentdiabetes mellitus and juvenile diabetes), dyslipidemia and metabolicsyndrome.

Ocular disorders include retinopathy (including diabetic retinopathy,proliferative retinopathy, non-proliferative retinopathy and retinopathyof prematurity), macular oedema (including diabetic macular oedema),age-related macular degeneration (ARMD), vascularisation (includingcorneal vascularisation and neovascularisation), retinal vein occlusion,and various forms of uveitis and keratitis.

Oncological disorders, which may be acute or chronic, includeproliferative disorders, especially cancer, and cancer-associatedcomplications (including skeletal complications, cachexia and anaemia).Particular categories of cancer include haematological malignancy(including leukaemia and lymphoma) and non-haematological malignancy(including solid tumour cancer, sarcoma, meningioma, glioblastomamultiforme, neuroblastoma, melanoma, gastric carcinoma and renal cellcarcinoma). Chronic leukaemia may be myeloid or lymphoid. Varieties ofleukaemia include lymphoblastic T cell leukaemia, chronic myelogenousleukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL),hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acutemyelogenous leukaemia (AML), myelodysplastic syndrome, chronicneutrophilic leukaemia, acute lymphoblastic T cell leukaemia,plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia,multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties oflymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicularlymphoma, MALT1 lymphoma and marginal zone lymphoma. Varieties ofnon-haematological malignancy include cancer of the prostate, lung,breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver,ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulatorsof TNFα function may also be used to increase the safety of the potentanticancer effect of TNF (see F. V. Hauwermeiren et al., J. Clin.Invest., 2013, 123, 2590-2603).

The present invention also provides a pharmaceutical composition whichcomprises a compound in accordance with the invention as describedabove, or a pharmaceutically acceptable salt or solvate thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (I) may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds of use in the present inventionmay be conveniently formulated in a suitable ointment containing theactive component suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Particular carriers include, for example, mineraloil, liquid petroleum, propylene glycol, polyoxyethylene,polyoxypropylene, emulsifying wax and water. Alternatively, thecompounds of use in the present invention may be formulated in asuitable lotion containing the active component suspended or dissolvedin one or more pharmaceutically acceptable carriers. Particular carriersinclude, for example, mineral oil, sorbitan monostearate, polysorbate60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanoland water.

For ophthalmic administration the compounds of use in the presentinvention may be conveniently formulated as micronized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present inventionmay be conveniently formulated as suppositories. These can be preparedby mixing the active component with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andso will melt in the rectum to release the active component. Suchmaterials include, for example, cocoa butter, beeswax and polyethyleneglycols.

The quantity of a compound of use in the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen and the condition of the patient to be treated.In general, however, daily dosages may range from around 10 ng/kg to1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01mg/kg to 40 mg/kg body weight, for oral or buccal administration, fromaround 10 ng/kg to 50 mg/kg body weight for parenteral administration,and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg toaround 1000 mg, for nasal administration or administration by inhalationor insufflation.

If desired, a compound in accordance with the present invention may beco-administered with another pharmaceutically active agent, e.g. ananti-inflammatory molecule such as methotrexate or prednisolone.

The compounds of formula (I) above may be prepared by a process whichcomprises reacting a compound of formula (III) with a compound offormula (IV):

wherein E, Q, Y, Z, R¹, R² and R³ are as defined above, and L¹represents a suitable leaving group.

The leaving group L¹ is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. a C₁₋₄ alkanol such as ethanol, or a cyclic ethersuch as 1,4-dioxane.

The compounds of formula (I) above wherein E represents —C(O)— may beprepared by a process which comprises reacting a compound of formula (V)with a compound of formula (VI):

wherein Q, Y, Z, R¹, R² and R³ are as defined above, R^(x) represents aC₁₋₄ alkyl group, e.g. methyl, and L² represents a suitable leavinggroup.

The leaving group L² is typically a halogen atom, e.g. bromo.

The reaction is conveniently effected at ambient or elevated temperaturein a suitable solvent, e.g. a dipolar aprotic solvent such asN,N-dimethylformamide, a hydrocarbon solvent such as toluene, or a C₁₋₄alkanol such as ethanol.

The intermediates of formula (V) above may be prepared by reacting acompound of formula (III) as defined above with a compound of formula(VII):

wherein Q, Z and IV are as defined above, and R^(y) represents a C₁₋₄alkyl group, e.g. methyl.

The reaction is conveniently effected at ambient or elevated temperaturein a suitable solvent, e.g. a dipolar aprotic solvent such asN,N-dimethylformamide, a hydrocarbon solvent such as toluene, or a C₁₋₄alkanol such as methanol.

The compounds of formula (I) above wherein E represents —CH(OH)— may beprepared by a process which comprises reacting a compound of formulaY-MgHal with a compound of formula (VIII):

wherein Q, Y, Z, R¹, R² and R³ are as defined above, and Hal representsa halogen atom.

The halogen atom Hal is typically bromo.

The reaction is conveniently effected at ambient temperature in asuitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

The intermediates of formula (VIII) above may be prepared by treating acompound of formula (IX):

wherein Q, Z, R¹, R² and R³ are as defined above; with(chloromethylene)dimethyl-iminium chloride (Vilsmeier reagent).

The reaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. a dipolar aprotic solvent such asN,N-dimethylformamide.

The compounds of formula (I) above wherein E represents —CH₂— and Yrepresents optionally substituted aryl or heteroaryl may be prepared bya process which comprises reacting a compound of formula Y¹—H with acompound of formula (X):

wherein Q, Z, R¹, R² and R³ are as defined above, and Y¹ represents arylor heteroaryl, either of which groups may be optionally substituted byone or more substituents; in the presence of a sulfonic acid derivative.

The sulfonic acid derivative of use in the foregoing reaction issuitably an organic sulfonic acid derivative such as methanesulfonicacid. The reaction is conveniently effected at an elevated temperaturein a suitable solvent, e.g. water.

The intermediates of formula (X) above may be prepared by treating acompound of formula (IX) as defined above with formaldehyde. Thereaction is conveniently effected at an elevated temperature in asuitable solvent, e.g. water.

The intermediates of formula (IX) above may be prepared by reacting acompound of formula (III) as defined above with a compound of formula(XI):

wherein Q, Z and L¹ are as defined above; under conditions analogous tothose described above for the reaction between compounds (III) and (IV).

The compounds of formula (I) above wherein -Q-Z represents —CH₂OH may beprepared by a process which comprises treating a compound of formula(XII):

wherein E, Y, R¹, R² and R³ are as defined above, and R^(z) represents aC₁₋₄ alkyl group, e.g. methyl; with a reducing agent.

The reducing agent of use in the foregoing reaction is suitably analkali metal borohydride such as lithium borohydride. The reaction isconveniently effected at ambient temperature in a suitable solvent, e.g.a cyclic ether such as tetrahydrofuran, or a C₁₋₄ alkanol such asmethanol, or a mixture thereof.

Alternatively, the reducing agent of use in the foregoing reaction maysuitably be diisobutylaluminum hydride. The reaction is convenientlyeffected at a temperature in the region of 0° C. in a suitable solvent,e.g. a cyclic ether such as tetrahydrofuran.

The intermediates of formula (XII) above may be prepared by reacting acompound of formula (III) as defined above with a compound of formula(XIII):

wherein E, Y, R^(z) and L¹ are as defined above; under conditionsanalogous to those described above for the reaction between compounds(III) and (IV).

The compounds of formula (I) above wherein E represents —N(H)— may beprepared by a process which comprises reacting a compound of formula(III) as defined above with an isocyanide derivative of formula Y—NC andan aldehyde derivative of formula OHC-Q-Z; in the presence of atransition metal catalyst.

The transition metal catalyst of use in the foregoing reaction issuitably a zirconium derivative, e.g. a zirconium halide such aszirconium(IV) chloride. The reaction is conveniently effected at anelevated temperature in a suitable solvent, e.g. a C₁₋₄ alkanol such asn-butanol.

The compounds of formula (I) above wherein Q represents —CH₂N(H)— may beprepared by a process which comprises reacting a compound of formulaZ—NH₂ with a compound of formula (XIV):

wherein E, Y, R¹, R² and R³ are as defined above; in the presence of areducing agent.

The reducing agent of use in the above reaction is suitably sodiumborohyride.

The intermediates of formula (XIV) may be prepared from thecorresponding compound of formula (I) wherein Q-Z represents —CH₂OH bytreatment with an oxidising agent such as Dess-Martin periodinane.

Where they are not commercially available, the starting materials offormula (III), (IV), (VI), (VII), (XI) and (XIII) may be prepared bymethods analogous to those described in the accompanying Examples, or bystandard methods well known from the art.

It will be understood that any compound of formula (I) initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula (I) bytechniques known from the art. By way of example, a compound of formula(I) wherein E represents —C(O)— may be converted into the correspondingcompound wherein E represents —CH(OH)— by treatment with a reducingagent such as sodium borohydride.

A compound of formula (I) wherein E represents —CH(OH)— may be convertedinto the corresponding compound wherein E represents —CH₂— by heatingwith elemental iodine and phosphinic acid in acetic acid; or by treatingwith triethylsilane and an acid, e.g. an organic acid such astrifluoroacetic acid, or a Lewis acid such as boron trifluoride diethyletherate; or by treating with chlorotrimethylsilane and sodium iodide;or by a two-step procedure which comprises: (i) treatment with thionylbromide; and (ii) treatment of the product thereby obtained with atransition metal catalyst, e.g. (2,2′-bipyridine)dichloro-ruthenium(II)hydrate, in the presence of diethyl1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylate (Hantzsch ester) anda base, e.g. an organic base such as N,N-diisopropylethylamine.

A compound of formula (I) wherein E represents —CH₂— may be convertedinto the corresponding compound wherein E represents —CH(CH₃)— bytreatment with a methyl halide, e.g. methyl iodide, in the presence of abase such as lithium hexamethyldisilazide.

A compound of formula (I) which contains a hydroxy group may bealkylated by treatment with the appropriate alkyl halide in the presenceof a base, e.g. sodium hydride, or silver oxide. A compound of formula(I) wherein -Q-Z represents —CH₂OH may be arylated in a two-stepprocedure which comprises: (i) treatment with thionyl chloride; and (ii)treatment of the chloro derivative thereby obtained with the appropriatearyl or heteroaryl hydroxide. A compound of formula (I) wherein -Q-Zrepresents —CH₂OH may be converted into the corresponding compound offormula (I) wherein -Q-Z represents —CH₂S—Z via a two-step procedurewhich comprises: (i) treatment with thionyl chloride; and (ii) treatmentof the chloro derivative thereby obtained with a compound of formulaZ—SH, typically in the presence of a base, e.g. an inorganic base suchas potassium carbonate. A compound of formula (I) wherein -Q-Zrepresents —CH₂OH may be converted into the corresponding compound offormula (I) wherein -Q-Z represents —CH₂CN via a two-step procedurewhich comprises: (i) treatment with thionyl chloride; and (ii) treatmentof the chloro derivative thereby obtained with a cyanide salt such assodium cyanide. A compound of formula (I) which contains hydroxy may beconverted into the corresponding fluoro-substituted compound bytreatment with diethylaminosulfur trifluoride (DAST) orbis(2-methoxyethyl)aminosulfur trifluoride (BAST). A compound of formula(I) which contains hydroxy may be converted into the correspondingdifluoro-substituted compound via a two-step procedure which comprises:(i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii)treatment of the carbonyl-containing compound thereby obtained withDAST.

A compound of formula (I) which contains an N—H moiety may be alkylatedby treatment with the appropriate alkyl halide, typically at an elevatedtemperature in an organic solvent such as acetonitrile; or at ambienttemperature in the presence of a base, e.g. an alkali metal carbonatesuch as potassium carbonate or cesium carbonate, in a suitable solvent,e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.Alternatively, a compound of formula (I) which contains an N—H moietymay be alkylated by treatment with the appropriate alkyl tosylate in thepresence of a base, e.g. an inorganic base such as sodium hydride, or anorganic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

A compound of formula (I) which contains an N—H moiety may be methylatedby treatment with formaldehyde in the presence of a reducing agent, e.g.sodium triacetoxyborohydride.

A compound of formula (I) which contains an N—H moiety may be acylatedby treatment with the appropriate acid chloride, e.g. acetyl chloride,or with the appropriate carboxylic acid anhydride, e.g. aceticanhydride, typically at ambient temperature in the presence of a base,e.g. an organic base such as triethylamine.

A compound of formula (I) which contains an N—H moiety may be convertedinto the corresponding compound wherein the nitrogen atom is substitutedby C₁₋₆ alkylsulphonyl, e.g. methylsulphonyl, by treatment with theappropriate C₁₋₆ alkylsulphonyl chloride, e.g. methanesulphonylchloride, or with the appropriate C₁₋₆ alkylsulphonic acid anhydride,e.g. methanesulphonic anhydride, typically at ambient temperature in thepresence of a base, e.g. an organic base such as triethylamine orN,N-diisopropylethylamine.

A compound of formula (I) substituted by amino (—NH₂) may be convertedinto the corresponding compound substituted by C₁₋₆ alkylsulphonylamino,e.g. methylsulphonylamino, or bis[(C₁₋₆)alkylsulphonyl]amino, e.g.bis(methylsulphonyl)amino, by treatment with the appropriate C₁₋₆alkylsulphonyl halide, e.g. a C₁₋₆ alkylsulphonyl chloride such asmethanesulphonyl chloride. Similarly, a compound of formula (I)substituted by hydroxy (—OH) may be converted into the correspondingcompound substituted by C₁₋₆ alkyl-sulphonyloxy, e.g.methylsulphonyloxy, by treatment with the appropriate C₁₋₆alkylsulphonyl halide, e.g. a C₁₋₆ alkylsulphonyl chloride such asmethanesulphonyl chloride.

A compound of formula (I) containing the moiety —S— may be convertedinto the corresponding compound containing the moiety —S(O)— bytreatment with 3-chloroperoxybenzoic acid. Likewise, a compound offormula (I) containing the moiety —S(O)— may be converted into thecorresponding compound containing the moiety —S(O)₂— by treatment with3-chloroperoxybenzoic acid. Alternatively, a compound of formula (I)containing the moiety —S— may be converted into the correspondingcompound containing the moiety —S(O)₂— by treatment with Oxone®(potassium peroxymonosulfate).

A compound of formula (I) containing an aromatic nitrogen atom may beconverted into the corresponding N-oxide derivative by treatment with3-chloroperoxybenzoic acid.

A bromophenyl derivative of formula (I) may be converted into thecorresponding optionally substituted 2-oxopyrrolidin-1-ylphenyl or2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-oneor oxazolidin-2-one, or an appropriately substituted analogue thereof.The reaction is conveniently effected at an elevated temperature in thepresence of copper(I) iodide, trans-N,N′-dimethylcyclohexane-1,2-diamineand an inorganic base such as potassium carbonate.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted aryl or heteroaryl moiety by treatment with theappropriately substituted aryl or heteroaryl boronic acid or a cyclicester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediolor neopentyl glycol. The reaction is typically effected in the presenceof a transition metal catalyst, e.g.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II),tetrakis(triphenyl-phosphine)palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as sodium carbonate orpotassium carbonate, or potassium phosphate.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted aryl, heteroaryl or heterocycloalkenyl moiety viaa two-step procedure which comprises: (i) reaction withbis(pinacolato)diboron or bis(neopentyl glycolato)diboron; and (ii)reaction of the compound thereby obtained with an appropriatelyfunctionalised halo- or tosyloxy-substituted aryl, heteroaryl orheterocycloalkenyl derivative. Step (i) is conveniently effected in thepresence of a transition metal catalyst such as[1,1′-bis-(diphenylphosphino)ferrocene]dichloropalladium(II), orbis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex. Step (ii) is conveniently effected in the presence of atransition metal catalyst such astetrakis-(triphenylphosphine)palladium(0), orbis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as sodium carbonate orpotassium carbonate.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted C₂₋₆ alkynyl moiety by treatment with anappropriately substituted alkyne derivative, e.g. 2-hydroxybut-3-yne.The reaction is conveniently accomplished with the assistance of atransition metal catalyst, e.g.tetrakis(triphenylphosphine)palladium(0), typically in the presence ofcopper(I) iodide and a base, e.g. an organic base such as triethylamine.

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents anoptionally substituted imidazol-1-yl moiety by treatment with theappropriately substituted imidazole derivative, typically in thepresence of copper(II) acetate and an organic base such asN,N,N′,N′-tetramethylethylenediamine (TMEDA).

A compound of formula (I) wherein R¹ represents halogen, e.g. bromo, maybe converted into the corresponding compound wherein R¹ represents2-(methoxycarbonyl)-ethyl via a two-step procedure which comprises: (i)reaction with methyl acrylate; and (ii) catalytic hydrogenation of thealkenyl derivative thereby obtained, typically by treatment with ahydrogenation catalyst, e.g. palladium on charcoal, under an atmosphereof hydrogen gas. Step (i) is typically effected in the presence of atransition metal catalyst, e.g. palladium(II) acetate orbis(dibenzylideneacetone)palladium(0), and a reagent such astri(ortho-tolyl)phosphine.

In general, a compound of formula (I) containing a —C═C— functionalitymay be converted into the corresponding compound containing a —CH—CH—functionality by catalytic hydrogenation, typically by treatment with ahydrogenation catalyst, e.g. palladium on charcoal, under an atmosphereof hydrogen gas, optionally in the presence of a base, e.g. an alkalimetal hydroxide such as sodium hydroxide.

A compound of formula (I) wherein R¹ represents 6-methoxypyridin-3-ylmay be converted into the corresponding compound wherein R¹ represents2-oxo-1,2-dihydropyridin-5-yl by treatment with pyridine hydrochloride;or by heating with a mineral acid such as hydrochloric acid. Byutilising similar methodology, a compound of formula (I) wherein R¹represents 6-methoxy-4-methylpyridin-3-yl may be converted into thecorresponding compound wherein R¹ represents4-methyl-2-oxo-1,2-dihydropyridin-5-yl; and a compound of formula (I)wherein R¹ represents 6-methoxy-5-methylpyridin-3-yl may be convertedinto the corresponding compound wherein R¹ represents3-methyl-2-oxo-1,2-dihydropyridin-5-yl.

A compound of formula (I) wherein R¹ represents2-oxo-1,2-dihydropyridin-5-yl may be converted into the correspondingcompound wherein R¹ represents 2-oxopiperidin-5-yl by catalytichydrogenation, typically by treatment with gaseous hydrogen in thepresence of a hydrogenation catalyst such as platinum(IV) oxide.

A compound of formula (I) containing an ester moiety, e.g. a C₂₋₆alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may beconverted into the corresponding compound containing a carboxy (—CO₂H)moiety by treatment with an acid, e.g. a mineral acid such ashydrochloric acid.

A compound of formula (I) containing an N-(tert-butoxycarbonyl) moietymay be converted into the corresponding compound containing an N—Hmoiety by treatment with an acid, e.g. a mineral acid such ashydrochloric acid, or an organic acid such as trifluoroacetic acid.

A compound of formula (I) containing an ester moiety, e.g. a C₂₋₆alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, mayalternatively be converted into the corresponding compound containing acarboxy (—CO₂H) moiety by treatment with a base, e.g. an alkali metalhydroxide selected from lithium hydroxide, sodium hydroxide andpotassium hydroxide; or an organic base such as sodium methoxide orsodium ethoxide.

A compound of formula (I) containing a carboxy (—CO₂H) moiety may beconverted into the corresponding compound containing an amide moiety bytreatment with the appropriate amine in the presence of a condensingagent such as 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide.

A compound of formula (I) containing a carbonyl (C═O) moiety may beconverted into the corresponding compound containing a —C(CH₃)(OH)—moiety by treatment with methylmagnesium bromide. Similarly, a compoundof formula (I) containing a carbonyl (C═O) moiety may be converted intothe corresponding compound containing a —C(CF₃)(OH)— moiety by treatmentwith (trifluoromethyl)trimethylsilane and cesium fluoride. A compound offormula (I) containing a carbonyl (C═O) moiety may be converted into thecorresponding compound containing a —C(CH₂NO₂)(OH)— moiety by treatmentwith nitromethane.

A compound of formula (I) containing a hydroxymethyl moiety may beconverted into the corresponding compound containing a formyl (—CHO)moiety by treatment with an oxidising agent such as Dess-Martinperiodinane. A compound of formula (I) containing a hydroxymethyl moietymay be converted into the corresponding compound containing a carboxymoiety by treatment with an oxidising agent such as tetrapropylammoniumperruthenate.

A compound of formula (I) wherein R¹ represents a substituent containingat least one nitrogen atom, which substituent is linked to the remainderof the molecule via a nitrogen atom, may be prepared by reacting acompound of formula (I) wherein R¹ represents halogen, e.g. bromo, withthe appropriate compound of formula R¹—H [e.g.1-(pyridin-3-yl)piperazine or morpholine]. The reaction is convenientlyeffected with the assistance of a transition metal catalyst, e.g.tris(dibenzylideneacetone)dipalladium(0), in the presence of anamination ligand such as2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-biphenyl (XPhos) or2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) and a base, e.g.an inorganic base such as sodium tert-butoxide. Alternatively, thereaction may be effected using palladium diacetate, in the presence of areagent such as[2′,6′-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane and abase, e.g. an inorganic base such as cesium carbonate.

A compound of formula (I) containing an oxo moiety can be converted intothe corresponding compound containing an ethoxycarbonylmethylidenemoiety by treatment with triethyl phosphonoacetate in the presence of abase such as sodium hydride.

A compound of formula (IIB) wherein R²¹ represents ethenyl may beprepared by reacting a compound of formula (IIB) wherein R²¹ representshalogen, e.g. chloro, with potassium vinyl trifluoroborate. The reactionis typically effected in the presence of a transition metal catalyst,e.g. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and abase, e.g. an organic base such as triethylamine.

A compound of formula (IIB) wherein R²¹ represents halogen, e.g. chloro,may be converted into the corresponding compound wherein R²¹ representsan optionally substituted C₄₋₇ cycloalkenyl moiety by treatment with theappropriately substituted cycloalkenyl boronic acid or a cyclic esterthereof formed with an organic diol, e.g. pinacol, 1,3-propanediol orneopentyl glycol. The reaction is typically effected in the presence ofa transition metal catalyst, e.g.bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethanecomplex, and a base, e.g. an inorganic base such as potassium carbonate.

A compound of formula (IIB) wherein R²¹ represents a substituentcontaining at least one nitrogen atom, which substituent is linked tothe remainder of the molecule via a nitrogen atom, may be prepared byreacting a compound of formula (IIB) wherein R²¹ represents halogen,e.g. chloro, with the appropriate compound of formula R²¹—H [e.g.2-methoxyethylamine, N-methyl-L-alanine, 2-aminocyclopentanecarboxylicacid, 3-aminocyclopentanecarboxylic acid,1-(aminomethyl)cyclopropanecarboxylic acid, methylazetidine-3-carboxylate, pyrrolidin-3-ol, pyrrolidine-3-carboxylic acid,piperidine-2-carboxylic acid, piperidine-3-carboxylic acid,4-(1H-tetrazol-5-yl)piperidine, piperazine,1-(methylsulfonyl)piperazine, piperazin-2-one,2-(piperazin-1-yl)propanoic acid, morpholine, morpholine-2-carboxylicacid, thiomorpholine, thiomorpholine 1,1-dioxide, 1,4-diazepan-5-one,2-oxa-5-azabicyclo[2.2.1]heptane or an appropriately substitutedazaspiroalkane], optionally in the presence of a base, e.g. an organicbase such as triethylamine or N,N-diisopropylethylamine and/or1-methyl-2-pyrrolidinone, or pyridine, or an inorganic base such aspotassium carbonate.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (I) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (I),e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation, and the desired enantiomer recovered, e.g.by treatment with an acid in the instance where the diastereomer is asalt. In another resolution process a racemate of formula (I) may beseparated using chiral HPLC. Moreover, if desired, a particularenantiomer may be obtained by using an appropriate chiral intermediatein one of the processes described above. Alternatively, a particularenantiomer may be obtained by performing an enantiomer-specificenzymatic biotransformation, e.g. an ester hydrolysis using an esterase,and then purifying only the enantiomerically pure hydrolysed acid fromthe unreacted ester antipode. Chromatography, recrystallisation andother conventional separation procedures may also be used withintermediates or final products where it is desired to obtain aparticular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit thebinding of a fluorescence conjugate to TNFα when tested in thefluorescence polarisation assay described below. Moreover, certaincompounds in accordance with this invention potently inhibitTNFα-induced NF-κB activation in the reporter gene assay describedbelow.

Fluorescence Polarisation Assay

Preparation of Compound (A)

1-(2,5-Dimethylbenzyl)-6-[4-(piperazin-1-ylmethyl)phenyl]-2-(pyridin-4-ylmethyl)-1H-benzimidazolehereinafter referred to as “Compound (A)” can be prepared by theprocedure described in Example 499 of WO 2013/186229 (published 19 Dec.2013); or by a procedure analogous thereto.

Preparation of Fluorescence Conjugate

Compound (A) (27.02 mg, 0.0538 mmol) was dissolved in DMSO (2 mL). 5(−6) Carboxy-fluorescein succinimyl ester (24.16 mg, 0.0510 mmol)(Invitrogen catalogue number: C1311) was dissolved in DMSO (1 mL) togive a bright yellow solution. The two solutions were mixed at roomtemperature, the mixture turning red in colour. The mixture was stirredat room temperature. Shortly after mixing a 20 μL aliquot was removedand diluted in a 80:20 mixture of AcOH:H₂O for LC-MS analysis on the1200RR-6140 LC-MS system. The chromatogram showed two closely elutingpeaks at retention times of 1.42 and 1.50 minutes, both with mass(M+H)⁺=860.8 amu, corresponding to the two products formed with the 5-and 6-substituted carboxyfluorescein group. A further peak at retentiontime 2.21 minutes had a mass of (M+H)⁺=502.8 amu, corresponding toCompound (A). No peak was observed for unreacted 5(−6)carboxyfluorescein succinimyl ester. The peak areas were 22.0%, 39.6%and 31.4% for the three signals, indicating a 61.6% conversion to thetwo isomers of the desired fluorescence conjugate at that time-point.Further 20 μL aliquots were extracted after several hours and then afterovernight stirring, diluted as before and subjected to LC-MS analysis.The percentage conversion was determined as 79.8% and 88.6% respectivelyat these time-points. The mixture was purified on a UV-directedpreparative HPLC system. The pooled purified fractions were freeze-driedto remove excess solvent. After freeze-drying, an orange solid (23.3 mg)was recovered, equivalent to 0.027 mmol of fluorescence conjugate,corresponding to an overall yield of 53% for the reaction andpreparative HPLC purification.

Inhibition of Binding of Fluorescence Conjugate to TNFα

Compounds were tested at 10 concentrations starting from 25 μM in afinal assay concentration of 5% DMSO, by pre-incubation with TNFα for 60minutes at ambient temperature in 20 mM Tris, 150 mM NaCl, 0.05% Tween20, before addition of the fluorescence conjugate and a furtherincubation for 20 hours at ambient temperature. The final concentrationsof TNFα and the fluorescence conjugate were 10 nM and 10 nM respectivelyin a total assay volume of 25 μL. Plates were read on a plate readercapable of detecting fluorescence polarisation (e.g. an Analyst HT platereader; or an Envision plate reader). An IC₅₀ value was calculated usingXLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the fluorescence polarisation assay, the compounds of theaccompanying Examples were all found to exhibit IC₅₀ values of 50 μM orbetter.

Reporter Gene Assay

Inhibition of TNFα-Induced NF-κB Activation

Stimulation of HEK-293 cells by TNFα leads to activation of the NF-κBpathway. The reporter cell line used to determine TNFα activity waspurchased from InvivoGen. HEK-Blue™ CD40L is a stable HEK-293transfected cell line expressing SEAP (secreted embryonic alkalinephosphatase) under the control of the IFNβ minimal promoter fused tofive NF-κB binding sites. Secretion of SEAP by these cells is stimulatedin a dose-dependent manner by TNFα, with an EC50 of 0.5 ng/mL for humanTNFα. Compounds were diluted from 10 mM DMSO stocks (final assayconcentration 0.3% DMSO) to generate a 10-point 3-fold serial dilutioncurve (e.g. 30,000 nM to 2 nM final concentration). Diluted compound waspreincubated with TNFα for 60 minutes prior to addition to a 384-wellmicrotitre plate and incubated for 18 h. The final TNFα concentration inthe assay plate was 0.5 ng/mL. SEAP activity was determined in thesupernatant using a colorimetric substrate, e.g. QUANTI-Blue™ orHEK-Blue™ Detection media (InvivoGen). Percentage inhibitions forcompound dilutions were calculated between a DMSO control and maximuminhibition (by excess control compound) and an IC₅₀ value calculatedusing XLfit™ (4 parameter logistic model) in ActivityBase.

When tested in the reporter gene assay, certain compounds of theaccompanying Examples were found to exhibit IC₅₀ values of 50 μM orbetter.

EXAMPLES

Abbreviations DCM: dichloromethane EtOAc: ethyl acetate MeOH: methanolDMSO: dimethylsulfoxide EtOH: ethanol Et₂O: diethyl ether DMF:N,N-dimethylformamide THF: tetrahydrofuran Pd(dppf)C1₂:[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd-118:dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) h: hourM: mass HPLC: High Performance Liquid Chromatography LCMS: LiquidChromatography Mass Spectrometry ES+: Electrospray Positive IonisationRT: retention time

Nomenclature

Compounds were named with the aid of ACD/Name Batch (Network) version11.01, and/or Accelrys Draw 4.0.

Analytical Conditions

Analytical HPLC

-   General Method-   Column: Waters, X Bridge, 20×2.1 mm, 2.5 μm-   Mobile Phase A: 10 mM ammonium formate in water+0.1% ammonia-   Mobile Phase B: acetonitrile+5% solvent A+0.1% ammonia-   Injection Volume: 5.0 μL-   Flow Rate: 1.00 mL/minute-   Gradient program: 5% B to 95% B in 4 minutes; hold till 5.00    minutes; at 5.10 minutes B conc. is 5% up to 6.5 minutes    pH 10 Method-   Column: Phenomenex, Gemini C18 (2.0 mm×100 mm, 3 μm column)-   Flow rate: 0.5 mL/minute-   Solvent A: 2 nM ammonium hydrogencarbonate in water-   Solvent B: acetonitrile-   Injection volume: 3 μL-   Column temperature: 50° C.-   UV detection wavelength: 215 nm-   Eluent: 0.00-5.50 minutes, constant gradient from 95% solvent A+5%    solvent B to 100% solvent B; 5.50-5.90 minutes, 100% solvent B.

General Method A

In a 10 mL microwave vial were taken Example 1 (200 mg, 0.54 mmol), therespective boronate acid or ester (1 equivalent) and sodium carbonate(172 mg, 1.63 mmol) in 1,4-dioxane (3 mL) and water (1 mL). The reactionmixture was degassed for 10 minutes and Pd(dppf)Cl₂ (44 mg, 0.054 mmol)was added, followed by degassing again for an additional 10 minutes. Thereaction mixture was heated at 125° C. for 2 h in a microwave reactor,then diluted with ethyl acetate (˜20 mL) and filtered through celite.The organic layer was dried over anhydrous sodium sulphate, concentratedin vacuo and submitted for preparative HPLC purification.

Intermediate 1 2-Bromo-1-[2-(difluoromethoxy)phenyl]ethanone

To a stirred solution of 2-(difluoromethoxy)acetophenone (5 g, 27.9mmol) in MeOH (15 mL) was added a solution of bromine (1.38 mL, 27.9mmol) in MeOH (10 mL). The reaction mixture was stirred at roomtemperature for 5-10 minutes before being heated at 75° C. for 1 h. Thereaction mixture was concentrated in vacuo, then the residue was dilutedwith DCM (20 mL) and washed with aqueous sodium bicarbonate solution (20mL). The aqueous layer was back-extracted with DCM (2×20 mL), then thecombined organic layers were dried over anhydrous sodium sulphate,filtered and concentrated in vacuo, to afford the title compound (6.6 g,92%) as a pale yellow oil. δ_(H) (500 MHz, CDCl₃) 7.83 (m, 1H), 7.58(td, 1H, J 8.3, 1.7 Hz), 7.34 (m, 1H), 7.20 (d, 1H, J 8.3 Hz), 6.64 (t,1H, J 72.9 Hz), 4.53 (s, 2H). HPLC-MS: MH+ m/z 265/267, RT 1.32 minutes.

Intermediate 2 N′-(6-Bromopyridazin-3-yl)-N,N-dimethylacetamidine

To a solution of 6-bromopyridazin-3-amine (2 g, 1.14 mmol) in DMF (10mL) was added N,N-dimethylacetamide dimethyl acetal (1.52 g, 1.14 mmol).The reaction mixture was heated in a sealed tube at 120° C. for 18 h,then concentrated in vacuo. The residue was diluted with DCM (20 mL) andwashed with aqueous sodium bicarbonate solution (10 mL). The aqueouslayer was back-extracted with DCM (2×20 mL), then the combined organiclayers were dried over anhydrous sodium sulphate, filtered, concentratedin vacuo and washed with Et₂O (2×20 mL), to afford the title compound(2.6 g, 96%) as a brown solid. δ_(H) (400 MHz, CDCl₃) 7.39 (d, 1H, J 8.8Hz), 6.83 (d, 1H, J 8.8 Hz), 3.11 (s, 6H), 2.12 (s, 3H). LCMS (ES+) 245(M+H)⁺, RT 1.83 minutes.

Intermediate 3(6-Bromo-2-methylimidazo[1,2-b]pyridazin-3-yl)[2-(difluoromethoxy)phenyl]methanone

A solution of Intermediate 1 (3.81 g, 14.4 mmol) and Intermediate 2 (3.5g, 14.4 mmol) in DMF (25 mL) was stirred at 100° C. for 18 h. Thereaction mixture was concentrated in vacuo, then the residue was dilutedwith DCM (20 mL) and washed with aqueous sodium bicarbonate solution (20mL). The aqueous layer was back-extracted with DCM (2×20 mL), then thecombined organic layers were dried over anhydrous sodium sulphate,filtered and concentrated in vacuo. The crude material was purified bycolumn chromatography (SiO₂, 10-25% EtOAc in hexane) to give the titlecompound (3.7 g, 68%) as a yellow solid. δ_(H) (400 MHz, CDCl₃) 7.79 (d,1H, J 9.6 Hz), 7.58-7.14 (m, 5H), 6.34 (t, 1H, J 73.2 Hz), 2.67 (s, 3H).LCMS (ES+) 381.95 (M+H)⁺, RT 2.43 minutes.

Intermediate 4(6-Bromo-2-methylimidazo[1,2-b]pyridazin-3-yl)[2-(difluoromethoxy)phenyl]methanol

To a stirred solution of Intermediate 3 (2.7 g, 7.09 mmol) in EtOH (20mL) was added sodium borohydride (0.32 g, 8.5 mmol). The reactionmixture was stirred at room temperature for 1 h, then quenched withaqueous ammonium chloride (3 mL). The EtOH was evaporated in vacuo, thenthe resulting aqueous material was extracted with DCM (3×20 mL). Thecombined organic layers were dried over anhydrous sodium sulphate,filtered and concentrated in vacuo, then washed with Et₂O (2×20 mL) togive the title compound (2.2 g, 81%) as a yellow solid. δ_(H) (400 MHz,DMSO-d₆) 7.96 (d, 1H, J 9.6 Hz), 7.90 (d, 1H, J 6.4 Hz), 7.36-6.77 (m,5H), 6.50 (d, 1H, J 4.0 Hz), 6.13 (d, 1H, J 4.4 Hz), 2.11 (s, 3H). LCMS(ES+) 386.1 (M+H)⁺, RT 2.00 minutes.

Intermediate 5 2-(Morpholin-4-yl)pyrimidin-5-ylboronic acid

A mixture of 2-chloropyrimidin-5-ylboronic acid (3 g, 19.0 mmol),morpholine (1.66 mL, 19.0 mmol) and triethylamine (1.67 mL, 19.2 mmol)in EtOH (20 mL) was stirred at 80° C. for 5 h. The reaction mixture wasconcentrated in vacuo and the residue was taken up in Et₂O(approximately 5 mL). Et₂O was added, and the triethylaminehydrochloride salt that crystallised out was filtered and discarded. Thefiltrate was concentrated in vacuo and water (approximately 10 mL) wasadded. The mixture was placed in a refrigerator for 1 h, after whichtime the resulting solid was filtered off, washed with the minimumamount of water and dried by suction, to give the title compound (2.7 g,68%) as an off-white solid. δ_(H) (DMSO-d₆) 8.64 (s, 2H), 8.08 (s, 2H),3.73 (m, 4H), 3.65 (m, 4H). LCMS (ES⁺) 210 (M+H)⁺, RT 0.15 minutes.

Intermediate 6 1-(5-Boronopyrimidin-2-yl)piperidine-4-carboxylic acid

2-Chloropyrimidin-5-ylboronic acid (2.00 g, 12.6 mmol) and isonipecoticacid (1.63 g, 12.6 mmol) were suspended in EtOH (25 mL). Triethylamine(1.78 mL, 12.65 mmol) was added and the mixture was heated at 80° C. for16 h. The reaction mixture was cooled to room temperature andconcentrated in vacuo to dryness. Water (30 mL) was added and thereaction mixture was swirled until the product completely dissolved. Onstanding, crystallisation occurred. The mixture was cooled in an icebath for 30 minutes, then filtered. The resultant solid was washedsparingly with water and dried under suction, then freeze-dried, to givethe title compound (1.90 g, 60%) as a white solid. δ_(H) (DMSO-d₆) 8.60(s, 2H), 8.06 (br s, 2H), 4.60-4.52 (m, 2H), 3.14-3.02 (m, 2H),2.60-2.54 (m, 1H), 1.90-1.80 (m, 2H), 1.55-1.39 (m, 2H). LCMS (ES⁺) 252(M+H)⁺.

Intermediate 7 [2-(3-Oxopiperazin-1-yl)pyrimidin-5-yl]boronic acid

2-Chloropyrimidin-5-ylboronic acid (1.0 g, 6.32 mmol) andpiperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL)and the mixture was heated at 100° C. under microwave irradiation for 45minutes. The supernatant liquid was decanted from the suspension and theresidue was triturated with MeOH and Et₂O. The resultant solids werefiltered off and dried under vacuum to afford the title compound (706mg, 30%) as a pale pink solid. LCMS (ES+) 223 (M+H)⁺.

Intermediate 8{2-[(1R,5S)-8-Methoxycarbonyl-3-azabicyclo[3.2.1]octan-3-yl]pyrimidin-5-yl}boronicacid

(1R,5S)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.2.1]octane-8-carboxylicacid (9.0 g, 35.3 mmol) was suspended in HCl solution (2.25M in MeOH).The reaction mixture was heated under reflux for 4 h, then allowed tocool to room temperature and concentrated in vacuo. To the resultingwhite solid was added 2-chloropyrimidin-5-ylboronic acid (5.58 g, 35.2mmol) and the mixture was suspended in EtOH (130 mL). Triethylamine(9.90 mL, 70.5 mmol) was added and the reaction mixture was heated at80° C. for 5 h. The reaction mixture was allowed to cool to roomtemperature, then water (30 mL) was added. The reaction mixture wasconcentrated to around one-third volume, then more water (100 mL) wasadded. An off-white solid precipitated out, which was filtered andwashed with water (2×30 mL) to afford the title compound (8.9 g, 86%) asan off-white powder. δ_(H) (300 MHz, DMSO-d₆) 8.59 (s, 2H), 8.02 (s,2H), 4.45 (dd, 2H, J 13.1, 3.4 Hz), 3.62 (s, 3H), 2.98 (br d, 2H, J 12.4Hz), 2.77 (s, 1H), 2.59 (br s, 2H), 1.66-1.63 (m, 2H), 1.38-1.33 (m,2H). LCMS (pH 10) (ES+) 292 (M+H)⁺, RT 0.97 minutes.

Intermediate 9 tert-Butyl4-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]-pyridazin-6-yl)pyrimidin-2-yl]piperazine-1-carboxylate

Prepared from Example 1 (300 mg, 0.81 mmol),{2-[4-(tert-butoxycarbonyl)-piperazin-1-yl]pyrimidin-5-yl}boronic acid(317 mg, 0.81 mmol), sodium carbonate (257 mg, 2.43 mmol) andPd(dppf)Cl₂ (66 mg, 0.081 mmol) in 1,4-dioxane (3 mL) and water (1 mL)according to General Method A. The reaction mixture was diluted withEtOAc (˜20 mL) and filtered through celite. The organic layer was driedover anhydrous sodium sulphate, concentrated in vacuo and purified bycolumn chromatography (SiO₂, 5-10% MeOH in DCM) to give the titlecompound (310 mg, 69%). LCMS (ES+) 552.3 (M+H)⁺, RT 3.36 minutes.

Intermediate 103-{[2-(Difluoromethoxy)phenyl]methyl}-2-methyl-6-[2-(piperazin-1-yl)pyrimidin-5-yl]-imidazo[1,2-b]pyridazine

To Intermediate 9 (310 mg, 0.56 mmol) was added 4M HCl/1,4-dioxane (10mL) at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 h, then concentrated in vacuo, to givethe title compound (252 mg, 100%). LCMS (ES+) 452.2 (M+H)⁺, RT 2.43minutes.

Intermediate 11 2-Bromo-1-(2,5-dichlorophenyl)ethanone

2,5-Dichloroacetophenone (20.9 g, 0.11 mol) was dissolved in Et₂O (300mL) and the reaction mixture was cooled to 0° C. Bromine (5.66 mL, 0.11mol) was added slowly dropwise and the reaction mixture was allowed towarm to room temperature over 20 minutes. The reaction mixture wastreated with saturated aqueous sodium bicarbonate solution (250 mL). Theorganic layer was separated, dried over anhydrous magnesium sulphate,filtered and concentrated in vacuo, yielding the title compound (20.0 g,68%) as a yellow oil. δ_(H) (DMSO-d₆) 7.94 (dd, 1H J 2.2, 0.3 Hz), 7.61(m, 2H), 4.88 (s, 2H).

Intermediate 12 N′-(6-Chloropyridazin-3-yl)-N,N-dimethylacetamidine

To a solution of 6-chloropyridazin-3-amine (5.0 g, 39 mmol) in MeOH (20mL) was added N,N-dimethylacetamide dimethyl acetal (7 mL, 48 mmol). Themixture was heated at 50° C. for 18 h, then cooled to room temperatureand concentrated in vacuo. The resulting solid was washed with Et₂O togive the title compound (5.4 g, 69%) as a beige solid. δ_(H) (400 MHz,DMSO-d₆) 7.58 (d, 1H, J 9.8 Hz), 7.04 (d, 1H, J 8.4 Hz), 3.06 (s, 6H),2.04 (s, 3H).

Intermediate 13(2,5-Dichlorophenyl)[2-methyl-6-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]-methanone

A mixture of Example 10 (1.04 g, 3.1 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (763mg, 3.7 mmol), Pd-118 (110 mg, 0.17 mmol) and 2M aqueous sodiumcarbonate solution (5 mL) in 1,4-dioxane (15 mL) was heated at 90° C.for 24 h. The reaction mixture was cooled to room temperature andpartitioned between EtOAc (100 mL) and water (100 mL). The aqueous layerwas separated and re-extracted into EtOAc (50 mL). The combined organiclayers were washed with water (50 mL) and brine (50 mL), then dried overanhydrous sodium sulphate, filtered and concentrated in vacuo. The crudematerial was washed with Et₂O and acetone to give the title compound(270 mg, 23%) as a crude dark solid, which was used in the next stepwithout further purification. δ_(H) (400 MHz, DMSO-d₆) 8.20 (d, 1H, J9.4 Hz), 8.01 (s, 1H), 7.71 (m, 4H), 7.29 (d, 1H, J 0.5 Hz), 3.86 (s,3H), 2.68 (s, 3H). LCMS (pH 10) 387 MH+, RT 1.58 minutes.

Intermediate 14(2,5-Dichlorophenyl)[2-methyl-6-(1-methylpyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]-methanol

A suspension of Intermediate 13 (250 mg, 0.6 mmol) in EtOH (8 mL) wastreated with sodium borohydride (25 mg, 0.66 mmol) and the mixture wasstirred at room temperature for 1 h. The suspension was treated withsaturated aqueous ammonium chloride solution (3 mL) and stirred for 1 h.The resulting solid was filtered, washed on a sinter with water (2×5 mL)and slurried with acetone, then concentrated in vacuo, to give the titlecompound (230 mg, 91%) as a white solid. δ_(H) (400 MHz, DMSO-d₆) 8.32(s, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.97 (d, 1H, J 9.4 Hz), 7.48 (d,1H, J 9.4 Hz), 7.39 (d, 2H, J 1.3 Hz), 6.36 (m, 2H), 3.92 (s, 3H), 2.27(s, 3H).

Intermediate 15 3-(Trifluoromethyl)azetidin-3-ol

To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (11.3 g, 58.4mmol) and (trifluoromethyl)trimethylsilane (9.22 g, 64.3 mmol) in THF(100 mL), cooled to approximately −5° C. on an ice/brine bath, was addedportionwise caesium fluoride (9.77 g, 64.3 mmol). The resultant mixturewas stirred at room temperature for 4 h. The reaction mixture wasquenched by the addition of saturated aqueous ammonium chloride solution(100 mL) and the aqueous phase was extracted with EtOAc (3×100 mL). Theorganic phase was separated and dried over sodium sulphate, thenfiltered. The volatiles were removed in vacuo. The resulting crude oilwas dissolved in DCM (100 mL) and trifluoroacetic acid (40 mL) wasadded. The mixture was stirred at ambient temperature for 4 h. Thevolatiles were removed in vacuo and the residue was azeotroped withtoluene (3×150 mL) to give the trifluoroacetate salt of the titlecompound (15 g) as a brown solid that was utilised without furtherpurification. δ_(H) (400 MHz, DMSO-d₆) 9.48 (s, 2H), 7.95 (d, J 0.3 Hz,1H), 4.28 (d, J 13.1 Hz, 2H), 4.06 (m, 2H).

Intermediate 161-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]-3-(trifluoromethyl)-azetidin-3-ol

To a solution of Intermediate 15 (12 g) in acetonitrile (150 mL) wereadded triethylamine (30 mL) and2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidine (16g). The reaction mixture was stirred at 65° C. for 18 h. The solventswere removed in vacuo, then the solid residue was triturated and washedwith distilled water. The resulting beige solid was dried under highvacuum to give the title compound (18.5 g) as a beige solid. δ_(H) (300MHz, DMSO-d₆) 8.53 (2H, s), 7.46 (1H, s), 4.33-4.31 (2H, m), 4.10-4.08(2H, m), 1.29 (12H, s). LCMS (ES⁺) 346.0 (M+H)⁺, RT 1.14 minutes.

Intermediate 17 6-Chloro-2-methyl-3-phenoxyimidazo[1,2-b]pyridazine

1-Bromo-1-phenoxypropan-2-one (prepared as described in EP-A-0056319;584 mg, 2.55 mmol) was dissolved in 1,4-dioxane (10 mL) and3-amino-6-chloropyridazine (300 mg, 2.32 mmol) was added. The mixturewas heated at 95° C. for 7 h. The reaction mixture was cooled anddiluted with ethyl acetate (120 mL), then washed with saturated aqueoussodium carbonate solution (50 mL). The organic layer was dried (sodiumsulfate) and concentrated in vacuo. The crude solid was purified bychromatography (SiO₂, 50-100% EtOAc in isohexanes) to give the titlecompound (460 mg, 76%) as a white solid. δ_(H) (400 MHz, DMSO-d₆) 8.13(d, J 9.5 Hz, 1H), 7.39-7.35 (m, 2H), 7.30 (d, J 9.5 Hz, 1H), 7.14 (m,1H), 6.98-6.94 (m, 2H), 2.28 (s, 3H). LCMS (pH 10) 260.6 (M+H)⁺, RT 2.17minutes.

Example 16-Bromo-3-[2-(difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazine

To a stirred solution of Intermediate 4 (2.2 g, 5.72 mmol) inacetonitrile (20 mL) was added sodium iodide (8.58 g, 57.2 mmol) and thereaction mixture was heated at 60° C. for 2 h. Chlorotrimethylsilane(0.62 g, 5.72 mmol) was added dropwise over 1 h and the reaction mixturewas stirred at 60° C. for an additional hour, then concentrated invacuo. The residue was diluted with DCM (20 mL) and washed with aqueoussodium bicarbonate solution (20 mL). The aqueous layer wasback-extracted with DCM (2×20 mL), then the combined organic layers weredried over anhydrous sodium sulphate, filtered and concentrated invacuo. The crude material was purified by column chromatography (SiO₂,10-25% EtOAc in hexane) to give the title compound (1.8 g, 84%) as abrown solid. δ_(H)(400 MHz, CD₃OD) 7.79 (d, 1H, J 9.2 Hz), 7.31-7.10 (m,5H), 6.86 (t, 1H, J 74.4 Hz), 4.37 (s, 2H), 2.41 (s, 3H). LCMS (ES+) 368(M+H)⁺, RT 2.54 minutes.

Example 23-[2-(Difluoromethoxy)benzyl]-2-methyl-6-[2-(morpholin-4-yl)pyrimidin-5-yl]-imidazo[1,2-b]pyridazine

Prepared from Example 1 (200 mg, 0.54 mmol), Intermediate 5 (113 mg,0.54 mmol), sodium carbonate (172 mg, 1.63 mmol) and Pd(dppf)Cl₂ (44 mg,0.054 mmol) in 1,4-dioxane (3 mL) and water (1 mL) according to GeneralMethod A. Purification of the crude product by preparative HPLC gave thetitle compound (117 mg, 48%) as an off-white solid. δ_(H) (DMSO-d₆) 8.99(s, 2H), 8.03 (d, 1H, J 9.2 Hz), 7.66 (d, 1H, J 9.6 Hz), 7.29-7.07 (m,5H), 4.36 (s, 2H), 3.80-3.68 (m, 8H), 2.40 (s, 3H). LCMS (ES+) 453.3(M+H)⁺, RT 2.45 minutes.

Example 31-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)piperidine-4-carboxylicacid

Prepared from Example 1 (200 mg, 0.54 mmol), Intermediate 6 (136 mg,0.54 mmol), sodium carbonate (172 mg, 1.63 mmol) and Pd(dppf)Cl₂ (44 mg,0.054 mmol) in 1,4-dioxane (3 mL) and water (1 mL) according to GeneralMethod A. Purification of the crude product by preparative HPLC gave thetitle compound (60 mg, 26%) as a grey solid. δ_(H) (DMSO-d₆) 8.95 (s,2H) 8.42 (s, 1H), 8.02 (d, 1H, J 9.6 Hz), 7.64 (d, 1H, J 8.8 Hz),7.29-7.07 (m, 5H), 4.54 (d, 2H, J 12.8 Hz), 4.36 (s, 2H), 3.15 (t, 3H, J12 Hz), 2.39 (s, 3H), 1.89 (d, 2H J 10.8 Hz), 1.52-1.49 (m, 2H). LCMS(ES+) 495.3 (M+H)⁺, RT 1.70 minutes.

Example 44-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)piperazin-2-one

Prepared from Example 1 (200 mg, 0.54 mmol), Intermediate 7 (120 mg,0.54 mmol), sodium carbonate (172 mg, 1.63 mmol) and Pd(dppf)Cl₂ (44 mg,0.054 mmol) in 1,4-dioxane (3 mL) and water (1 mL) according to GeneralMethod A. Purification of the crude product by preparative HPLC gave thetitle compound (8 mg, 3%) as a white solid. δ_(H) (DMSO-d₆) 9.02 (s,2H), 8.15 (br s, 1H), 8.04 (d, 1H, J 9.2 Hz), 7.67 (d, 1H, J 9.2 Hz),7.29-7.07 (m, 5H), 4.36 (s, 2H), 4.26 (s, 2H), 3.99 (m, 2H), 2.66 (m,2H), 2.40 (s, 3H). LCMS (ES+) 466.2 (M+H)⁺, RT 2.06 minutes.

Example 54-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}benzene-sulfonamide

Prepared from Example 1 (200 mg, 0.54 mmol), 4-sulfamoylphenylboronicacid pinacol ester (153 mg, 0.54 mmol), sodium carbonate (172 mg, 1.63mmol) and Pd(dppf)Cl₂ (44 mg, 0.054 mmol) in 1,4-dioxane (3 mL) andwater (1 mL) according to General Method A. Purification of the crudeproduct by preparative HPLC gave the title compound (73 mg, 30%) as anoff-white solid. δ_(H) (DMSO-d₆) 8.22 (d, 2H, J 8.8 Hz), 8.11 (d, 1H, J9.2 Hz), 7.96 (d, 2H, J 8.0 Hz), 7.78 (d, 1H, J 9.6 Hz), 7.48 (br s,2H), 7.34-7.09 (m, 5H), 4.41 (s, 2H), 2.43 (s, 3H). LCMS (ES+) 445.2(M+H)⁺, RT 2.20 minutes.

Example 63-[2-(Difluoromethoxy)benzyl]-2-methyl-6-{2-[4-(methylsulfonyl)piperazin-1-yl]-pyrimidin-5-yl}imidazo[1,2-b]pyridazine

To a solution of Intermediate 10 (250 mg, 0.55 mmol) in DCM (5 mL) wasadded triethylamine (0.23 mL, 1.65 mmol) and resulting mixture wasstirred for 10 minutes at 0° C. Mesyl chloride (63 mg, 0.55 mmol) wasthen added and the reaction mixture was allowed to stir at roomtemperature for 18 h. The reaction mixture was diluted with water (5mL), then extracted with EtOAc (3×10 mL). The combined organic layerswere dried over anhydrous sodium sulphate, filtered and concentrated invacuo. The crude material was purified by column chromatography (SiO₂,5-10% MeOH in DCM) to give the title compound (50 mg, 9%) as a whitesolid. δ_(H) (DMSO-d₆) 9.01 (s, 2H), 8.05 (d, 1H, J 9.6 Hz), 7.69 (d,1H, J 9.6 Hz), 7.44-7.07 (m, 5H), 4.37 (s, 2H), 3.96 (m, 4H), 3.32-3.21(m, 4H), 2.90 (s, 3H), 2.41 (s, 3H). LCMS (ES+) 530.3 (M+H)⁺, RT 2.4minutes.

Example 7 Methyl(1R,5S)-3-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]-pyridazin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylate

To a suspension of Example 1 (202 mg, 0.55 mmol) and Intermediate 8 (238mg, 0.82 mmol) in 1,4-dioxane (7 mL) and 2M aqueous sodium carbonatesolution (1 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloridedichloromethane complex (18 mg, 0.022 mmol). The reaction mixture wasdegassed (3× vacuum/N₂) and heated at 100° C. for 3 h. The reactionmixture was then cooled to room temperature, diluted with EtOAc (25 mL)and washed with water (2×25 mL). The aqueous layer was back-extractedwith EtOAc (2×25 mL), then the combined organic layers were dried overanhydrous sodium sulphate, filtered and concentrated in vacuo. The crudematerial was purified by column chromatography (SiO₂, 40-100% EtOAc inhexane), and the resulting material was freeze-dried fromacetonitrile/water, to give the title compound (232 mg, 79%) as anoff-white solid. δ_(H) (300 MHz, DMSO-d₆) 8.95 (s, 2H), 8.03 (d, 1H, J9.5 Hz), 7.65 (d, 1H, J 9.5 Hz), 7.25-7.31 (m, 2H), 7.26 (t, 1H, J 74.1Hz), 7.10-7.20 (m, 2H), 4.50 (dd, 2H, J 13.2, 3.5 Hz), 4.37 (s, 2H),3.64 (s, 3H), 3.09 (d, 2H, J 12.3 Hz), 2.83 (s, 1H), 2.61-2.67 (m, 2H),2.40 (s, 3H), 1.64-1.73 (m, 2H), 1.36-1.44 (m, 2H). LCMS (ES+) (pH 10)535 (M+H)⁺, RT 2.74 minutes.

Example 8(1R,5S)-3-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylicacid

To a stirred solution of Example 7 (218 mg, 0.41 mmol) in THF (11 mL)was added lithium hydroxide monohydrate (69 mg, 1.64 mmol) in water (4mL). The reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was then partitioned between EtOAc (20 mL) and water(10 mL), and the layers were separated. The aqueous layer was acidifiedto pH 3 with 2M HCl. The yellow solid which slowly precipitated wasfiltered off, washed with Et₂O and dried under vacuum. The crudematerial was purified by column chromatography (SiO₂, 0-20% MeOH inDCM), and the residue was freeze-dried from acetonitrile/methanol/water,to give the title compound (124 mg, 59%) as an off-white solid. δ_(H)(300 MHz, DMSO-d₆) 12.12-12.36 (m, 1H), 8.95 (s, 2H), 8.03 (d, 1H, J 9.5Hz), 7.65 (d, 1H, J 9.5 Hz), 7.25-7.32 (m, 2H), 7.26 (t, 1H, J 74.3 Hz),7.10-7.21 (m, 2H), 4.46-4.55 (m, 2H), 4.37 (s, 2H), 3.04-3.10 (m, 2H),2.67-2.71 (m, 1H), 2.59-2.65 (m, 2H), 2.40 (s, 3H), 1.66-1.75 (m, 2H),1.34-1.42 (m, 2H). LCMS (ES+) (pH 10) 521 (M+H)⁺, RT 2.16 minutes.

Example 92-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)propan-2-ol

To a suspension of Example 1 (200 mg, 0.54 mmol) and2-(1-hydroxy-1-methyl-ethyl)pyrimidine-5-boronic acid pinacol ester (216mg, 0.82 mmol) in 1,4-dioxane (5 mL) and 2M aqueous sodium carbonatesolution (1 mL) was added[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloridedichloromethane complex (18 mg, 0.022 mmol). The reaction mixture wasdegassed (3× vacuum/N₂) and heated at 100° C. for 2 h. The reactionmixture was then cooled to room temperature, diluted with EtOAc (25 mL)and washed with water (25 mL). The aqueous layer was back-extracted withEtOAc (2×25 mL). The combined organic layers were dried over anhydrousmagnesium sulphate, filtered and concentrated in vacuo. The crudematerial was purified by column chromatography (SiO₂, 0-10% MeOH inEtOAc), and the residue was freeze-dried from acetonitrile/water, togive the title compound (231 mg, 100%) as a pale yellow solid. δ_(H)(300 MHz, DMSO-d₆) 9.37 (s, 2H), 8.17 (d, 1H, J 9.4 Hz), 7.83 (d, 1H, J9.4 Hz), 7.26-7.34 (m, 2H), 7.26 (t, 1H, J 74.3 Hz), 7.11-7.21 (m, 2H),5.18 (s, 1H), 4.42 (s, 2H), 2.43 (s, 3H), 1.54 (s, 6H). LCMS (ES+) (pH10) 426 (M+H)⁺, RT 2.10 minutes.

Example 10(6-Chloro-2-methylimidazo[1,2-b]pyridazin-3-yl)(2,5-dichlorophenyl)methanone

A solution of Intermediate 11 (5.4 g, 27 mmol) in EtOH (40 mL) wastreated with Intermediate 12 (9.5 g, 36 mmol). The mixture was heated at75° C. for 1.5 h, then stood at room temperature overnight. The mixturewas concentrated in vacuo and the residue was partitioned between EtOAcand saturated aqueous sodium bicarbonate solution. The organic layerswere separated and the aqueous layer was extracted into EtOAc. Thecombined organic layers were washed with water and brine, then driedover anhydrous sodium sulphate, filtered and concentrated in vacuo. Thecrude material was purified by column chromatography (SiO₂, 0-50% EtOAcin hexane) to give the title compound (6.2 g, 59%) as a pale oil. δ_(H)(400 MHz, DMSO-d₆) 8.31 (s, 1H), 8.28 (s, 1H), 7.68-7.60 (m, 3H), 2.51(s, 3H).

Example 113-[(2,5-Dichlorophenyl)methyl]-2-methyl-6-(1-methylpyrazol-4-yl)imidazo[1,2-b]-pyridazine

To a suspension of Intermediate 14 (205 mg, 0.53 mmol) andhypophosphorous acid (0.1 mL) in acetic acid (1.5 mL) was added iodine(25 mg). The reaction mixture was heated at 90° C. for 5 h, then cooledto room temperature and concentrated in vacuo. The residue waspartitioned between DCM (10 mL) and saturated aqueous sodium bicarbonatesolution (10 mL). The organic layer was separated, dried over anhydroussodium sulphate, decanted and concentrated in vacuo. The resulting whitesolid was purified by preparative LC to give the title compound (105 mg,58%) as a white solid. δ_(H) (400 MHz, DMSO-d₆) 8.35 (s, 1H), 8.03 (d,1H, J 0.3 Hz), 7.97 (d, 1H, J 9.4 Hz), 7.48 (m, 3H), 7.34 (dd, 1H, J8.5, 2.6 Hz), 4.41 (s, 2H), 3.91 (s, 3H), 2.40 (s, 3H). LCMS (pH 10) 373MH+, RT 1.65 minutes.

Example 121-[5-(2-methyl-3-phenoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl]-3-(trifluoromethyl)azetidin-3-ol

Prepared from Intermediate 17 (200 mg, 0.77 mmol), Intermediate 16 (1.08mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethanecomplex (26 mg, 0.031 mmol), 1,4-dioxane (10 mL) and 2M aqueous sodiumcarbonate solution (2 mL) by General Method A to give the title compound(145 mg, 43%) as an off-white solid. δ_(H) (400 MHz, DMSO-d₆) 8.85 (s,2H), 8.11 (d, J 9.5 Hz, 1H), 7.71 (d, J 9.5 Hz, 1H), 7.47 (s, 1H),7.38-7.34 (m, 2H), 7.13 (m, 1H), 7.01-6.98 (m, 2H), 4.34 (d, J 11.1 Hz,2H), 4.11 (d, J 11.1 Hz, 2H), 2.34 (s, 3H). LCMS (pH 10) 443.6 (M+H)⁺,RT 2.23 minutes.

The invention claimed is:
 1. A compound represented by formula (IIB) oran N-oxide thereof, or a pharmaceutically acceptable salt or solvatethereof:

wherein V represents C—R²² or N; R¹² represents hydrogen, fluoro,chloro, trifluoromethyl, methyl or ethoxycarbonylethyl; R¹⁵ and R¹⁶independently represent hydrogen, halogen, cyano, nitro, C₁₋₆ alkyl,trifluoromethyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₆ alkylamino, di(C₁₋₆)alkylamino, arylamino, C₂₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, formyl, C₂₋₆ alkylcarbonyl,C₃₋₆ cycloalkylcarbonyl, C₃₋₆ heterocycloalkylcarbonyl, carboxy, C₂₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl,di(C₁₋₆)alkylaminocarbonyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl ordi(C₁₋₆)alkylaminosulfonyl; R²¹ represents hydroxy(C₁₋₆)alkyl; or R²¹represents (C₃₋₇)heterocycloalkyl, or (C₄₋₉)heterobicycloalkyl, eitherof which groups may be optionally substituted by one, two or threesubstituents independently selected from trifluoromethyl, hydroxy, C₁₋₆alkylsulphonyl, oxo, carboxy and C₂₋₆ alkoxycarbonyl; R²² representshydrogen, halogen or C₁₋₆ alkyl; R²³ represents hydrogen, C₁₋₆ alkyl,trifluoromethyl or C₁₋₆ alkoxy; E represents —O—, —CH₂— or —C(O)—; Qrepresents —CH₂—; Z represents hydrogen or methyl; R⁴ and R⁵independently represent hydrogen or C₁₋₆ alkyl.
 2. The compound asclaimed in claim 1 wherein R²¹ represents hydroxy(C₁₋₆)alkyl.
 3. Thecompound as claimed in claim 1 represented by formula (IIC), (IIE), or(IIL) or an N-oxide thereof, or a pharmaceutically acceptable salt orsolvate thereof:

wherein T represents —CH₂— or —CH₂CH₂—; U represents C(O) or S(O)₂; Wrepresents O, N(R³¹) or C(R³²)(R³³); -M- represents —CH₂— or —CH₂CH₂—;R³¹ represents C₁₋₆ alkylsulphonyl; R³² represents hydrogen, hydroxy,C₁₋₆ alkylsulphonyl, carboxy, or C₂₋₆ alkoxycarbonyl; R³³ representshydrogen; E represents —O—, —CH₂— or —C(O)—; Q represents —CH₂—; Zrepresents hydrogen or methyl; R⁴ and R⁵ independently representhydrogen or C₁₋₆ alkyl; R¹² represents represents hydrogen, fluoro,chloro, trifluoromethyl, methyl or ethoxycarbonylethyl; R¹⁵ representshydrogen, halogen, C₁₋₆ alkyl, trifluoromethyl, C₁₋₆ alkoxy,difluoromethoxy or trifluoromethoxy; and R¹⁶ represents hydrogen,halogen, cyano, C₁₋₆ alkyl, trifluoromethyl, difluoromethoxy or amino.4. The compound as claimed in claim 1 wherein E represents —CH₂—.
 5. Acompound as claimed in claim 1 wherein R¹⁵ represents difluoromethoxy.6. A compound which is any one of3-[2-(Difluoromethoxy)benzyl]-2-methyl-6-[2-(morpholin-4-yl)pyrimidin-5-yl]-imidazo[1,2-b]pyridazine;1-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)piperidine-4-carboxylicacid;4-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)piperazin-2-one;3-[2-(Difluoromethoxy)benzyl]-2-methyl-6-{2-[4-(methylsulfonyl)piperazin-1-yl]-pyrimidin-5-yl}imidazo[1,2-b]pyridazine;Methyl(1R,5S)-3-[5-(3-{[2-(difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]-pyridazin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylate;(1R,5S)-3-[5-(3-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl]-3-azabicyclo[3.2.1]octane-8-carboxylicacid;2-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-b]pyridazin-6-yl}pyrimidin-2-yl)propan-2-ol;or1-[5-(2-methyl-3-phenoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidin-2-yl]-3-(trifluoro-methyl)azetidin-3-ol.7. A pharmaceutical composition comprising a compound of formula (IIB)as defined in claim 1 or an N-oxide thereof, or a pharmaceuticallyacceptable salt or solvate thereof, in association with apharmaceutically acceptable carrier.
 8. The pharmaceutical compositionas claimed in claim 7 further comprising an additional anti-inflammatoryagent.